Professor Angelica Ronald

Professor of Psychology and Genetics
Fridays 11am-12pm; 2pm-3pm

Academic and research departments

School of Psychology.


Areas of specialism

Neurodevelopment; Quantitative Genetics; Infant development; Autism; ADHD; Adolescent mental health; Behaviour Genetics

My qualifications

BA (First class) Experimental Psychology
University of Oxford
PhD (Quantitative Genetics)
King's College London


Postgraduate research supervision



Angelica Rachel Ronald, Joshua A Gordon, Till Andlauer, Lukoye Atwoli, Na Cai, Thomas Lehner, Michel Nivard, Kathryn Roeder (2023)Delineating Additional Risk Factors, In: Exploring and Exploiting Genetic Risk for Psychiatric Disorders MIT Press

This chapter highlights paths, processes, and considerations that become important as we build on the initial success of large genome-wide association studies of psychiatric disorders. As such, it largely focuses on research on common genetic variation and human genetic research. It proposes directing research toward interrogating how genetic variation acts on the developing brain. For this reason, it discusses the potential value and pitfalls of using developmental, circuit-based, and quantitative symptom-based phenotypes in parallel to the traditional approach of reliance on binary diagnoses in genetic research designs. With respect to heterogeneity and co-occurrence present in psychiatric disorders, analytic approaches are outlined that can advance understanding, improve gene discovery, and potentially infl uence nosology. It argues that increasing cohort diversity is nonnegotiable: it is essential to improve gene discovery, translation, social justice, and research equity. Furthermore, a range of methods that interrogate the processes of environmental risk, gene–environment correlation, and gene–environment interaction enable a more accurate understanding of direct genetic eff ects and of how environments operate together with genetic risk for psychiatric disorders. Far from being a diversion, these environmentally informed methods are likely to catalyze biological insights. To this end, considerations for optimal future experimental study designs are discussed , outlining their characteristics and the prioritized approaches. The overarching goal is to deliver, through gene discovery research, translational benefi ts for individuals living with neurodevelopmental conditions and psychiatric disorders.

Ana Maria Portugal, Charlotte Viktorsson, Mark Taylor, Kristiina Tammimies, Angelica Rachel Ronald, Terje Falck-Ytter (2023)Infants' looking preferences for social versus non-social objects reflect genetic variation, In: Nature Human Behaviour Nature Research

To what extent do individual differences in infants’ early preference for faces versus non-facial objects reflect genetic and environmental factors? In a sample of 536 5-month-old same-sex twins, we assessed attention to faces using eye-tracking in two ways: initial orienting to faces at the start of the trial (thought to reflect subcortical processing) and sustained face preference throughout the trial (thought to reflect emerging attention control). We show that both face orienting and preference were heritable (h² = .19, CI: .04-.33; h² = .46, CI: .33-.57, respectively); while shared environment was statistically nonsignificant. Face preference was associated positively with later parent-reported verbal competence (β = 0.14, p = .014). This is the first study to show that individual differences in young infants’ selection of perceptual input – social versus non-social – are heritable, providing a new developmental perspective on gene-environment interplay occurring at the level of eye movements.

Soo Hyun Rhee, Angelica Ronald (2014)Behavior genetics of psychopathology Springer

As a dynamic, interdisciplinary field, behavior genetics and its evolution are being followed closely by scientists across the psychological and medical domains. The discoveries surrounding the human genome and the advancement in molecular genetic technologies have led to studies becoming increasingly sophisticated and yielding yet more conclusive and useful results. This is certainly the case in the area of child and adult psychopathology. Behavior Genetics of Psychopathology summarizes the state of the field, examining the role of genes and environment as they affect common neurodevelopmental and psychiatric conditions. Emphasizing key research areas (comorbidities, twin studies, the integration of methods), the book assesses the current literature, offers up-to-date findings, sorts through lingering controversies, and identifies a clear future agenda for the field. Expertly-written chapters focus on issues of general salience that shape behavior genetics of psychopathology, as well as specific disorders of major clinical importance, among them: ADHD: the view from quantitative genetic research. Autism spectrum disorders and their complex heterogeneity Genetic influences on anxiety and depression in childhood and adolescence. Evidence for etiologically-defined subgroups within the construct of antisocial behavior. Sleep and psychopathology: the reasons for their co-occurrence. Behavioral genetic approaches to the etiology of comorbidity. Epigenetics of psychopathology. This combination of timeliness and depth of coverage make Behavior Genetics of Psychopathology a frontline resource for behavior geneticists, psychologists, psychiatrists, and neuroscientists, and is perfectly suited to graduate students looking to join these fields.

Laura Havers, Alastair Cardno, Daniel Freeman, Angelica Ronald (2022)The Latent Structure of Negative Symptoms in the General Population in Adolescence and Emerging Adulthood, In: Schizophrenia bulletin open3(1)pp. sgac009-sgac009 Oxford University Press

Abstract Negative symptoms predict adverse outcomes within psychotic disorders, in individuals at high-risk for psychosis, and in young people in the community. There is considerable interest in the dimensional structure of negative symptoms in clinical samples, and accumulating evidence suggests a 5-factor structure. Little is known about the underlying structure of negative symptoms in young people despite the importance of this developmental stage for mental health. We used confirmatory factor analysis to test the structure of parent-reported negative symptoms at mean ages 16.32 (SD 0.68, N = 4974), 17.06 (SD 0.88, N = 1469) and 22.30 (SD 0.93, N = 5179) in a community sample. Given previously reported associations between total negative symptoms and genome-wide polygenic scores (GPS) for major depressive disorder (MDD) and schizophrenia in adolescence, we assessed associations between individual subdomains and these GPSs. A 5-factor model of flat affect, alogia, avolition, anhedonia, and asociality provided the best fit at each age and was invariant over time. The results of our linear regression analyses showed associations between MDD GPS with avolition, flat affect, anhedonia, and asociality, and between schizophrenia GPS with avolition and flat affect. We showed that a 5-factor structure of negative symptoms is present from ages 16 to 22 in the community. Avolition was most consistently associated with polygenic liability to MDD and schizophrenia, and alogia was least associated. These findings highlight the value of dissecting negative symptoms into psychometrically derived subdomains and may offer insights into early manifestation of genetic risk for MDD and schizophrenia.

Angelica Rachel Ronald (2007)Errata, In: Child development78(3)pp. 1033-1034 Blackwell Publishing
Angelica Ronald, Rosa Hoekstra (2014)Progress in Understanding the Causes of Autism Spectrum Disorders and Autistic Traits: Twin Studies from 1977 to the Present Day, In: Behavior Genetics of Psychopathologypp. 33-65 Springer New York

Researchers continue to pursue a better understanding of the symptoms, comorbidities, and causes of autism spectrum disorders. In this chapter, we review the twin studies of autism spectrum disorders (ASDs) and autistic traits that have contributed to this endeavor. These twin studies have reported on the heritability of ASDs and autistic traits in different populations and using different measurement and age groups. These studies reveal that the etiology of clinical autism and autistic traits assessed in the general population is more similar than different, which contributes to the question of where the boundary lies between ASD and typical development. These studies have also stimulated debates and new hypotheses regarding what causes ASDs; their comorbidity with intellectual disability, language delay, and psychiatric disorders such as ADHD; and why ASDs show substantial symptom heterogeneity. Lastly, methodological assumptions of the twin design are given consideration in relation to autism research. We conclude with suggesting a range of future research directions for studying ASDs and related phenotypes.

Mark J. Taylor, Tony Charman, Angelica Ronald (2015)Where are the strongest associations between autistic traits and traits of ADHD? evidence from a community-based twin study, In: European child & adolescent psychiatry24(9)pp. 1129-1138 Springer Nature

Autism spectrum conditions (ASC) and attention-deficit/hyperactivity disorder (ADHD) regularly co-occur. Twin studies increasingly indicate that these conditions may have overlapping genetic causes. Less is known about the degree to which specific autistic traits relate to specific behaviours characteristic of ADHD. We hence tested, using the classical twin design, whether specific dimensional autistic traits, including social difficulties, communication atypicalities and repetitive behaviours, would display differential degrees of aetiological overlap with specific traits of ADHD, including hyperactivity/impulsivity and inattention. Parents of approximately 4,000 pairs of 12-year-old twins completed the Childhood Autism Spectrum Test and Conners' Parent Rating Scale. These measures were divided into subscales corresponding to different types of autistic and ADHD behaviours. Twin model fitting suggested that the degree of genetic overlap was particularly strong between communication difficulties and traits of ADHD (genetic correlations = .47-.51), while repetitive behaviours and social difficulties showed moderate (genetic correlations = .12-.33) and modest (.05-.11) genetic overlap respectively. Environmental overlap was low across all subscales (correlations = .01-.23). These patterns were also apparent at the extremes of the general population, with communication difficulties showing the highest genetic overlap with traits of ADHD. These findings indicate that molecular genetic studies seeking to uncover the shared genetic basis of ASC and ADHD would benefit from taking a symptom-specific approach. Furthermore, they could also help to explain why studies of the communication abilities of individuals with ASC and ADHD have produced overlapping findings.

Aline Scherff, Mark Taylor, Thalia C. Eley, Francesca Happe, Tony Charman, Angelica Ronald (2014)What Causes Internalising Traits and Autistic Traits to Co-occur in Adolescence? A Community-Based Twin Study, In: Journal of abnormal child psychology42(4)pp. 601-610 Springer Nature

Autism shows a high degree of comorbidity with anxiety disorders. Adolescence is a time of increased stress and vulnerability to internalising problems. This study addresses for the first time the degree of genetic and environmental overlap between autistic traits (total measure and subscales) and internalising traits in a community-based adolescent twin sample. Parents of 12-14-year-old twins (N = 3,232 pairs; 3,460 males, 3,004 females) reported on the twins' internalising and autistic traits. Autistic trait subscales were created using principal component analysis. Bivariate twin model-fitting was conducted. Autistic and internalising traits correlated moderately (r = 0.30). Genetic influences on individual traits were substantial but genetic overlap between traits was moderate (genetic correlation: males = 0.30, females = 0.12). Shared environmental influences were low for internalising traits and moderate for autistic traits, and showed considerable overlap (shared environmental correlation: males = 0.53, females = 1). Nonshared environmental influences were moderate for internalising traits and low for autistic traits and showed low overlap. A multiple component solution was found for autistic traits and of the derived subscales, autistic-like 'Social Unease' showed the most phenotypic and genetic overlap with internalising traits.

Monica Siqueiros Sanchez, Angelica Ronald, Luke Mason, Emily J.H. Jones, Sven Bölte, Terje Falck-Ytter (2021)Visual disengagement in young infants in relation to age, sex, SES, developmental level and adaptive functioning, In: Infant behavior & development63pp. 101555-101555 Elsevier Inc

•We conducted a study of attention (visual disengagement) in 436 five-month-old infants.•Females were faster in the Gap condition than males implicating potential sex differences in cognitive control.•Infants with higher socioeconomic status (SES) were slower than lower SES infants in the overlap condition.•Visual disengagement was not associated with developmental level nor with adaptive functioning. Visual attention plays a key role in infants’ interaction with the environment, and shapes their behavioral and brain development. As such, early problems with flexibly switching gaze from one stimulus to another (visual disengagement) have been hypothesized to lead to developmental difficulties (e.g. joint attention and social skills) over time. This study aimed to identify cross-sectional associations between performance in the Gap task (gaze shift latencies and visual attention disengagement) and measures of development and adaptive behavior in conjunction to any sex or socioeconomic status effects in infancy. We measured visual attention disengagement in 436 5-month-old infants and calculated its association with cognitive developmental level, adaptive behaviours, socioeconomic status (SES) and biological sex. In the Gap task, participants must redirect their gaze from a central stimulus to an appearing peripheral stimulus. The three experimental conditions of the task (Gap, Baseline and Overlap) differ on the timepoint when the central stimuli disappears in relation to the appearance of the peripheral stimulus: 200 ms before the peripheral stimulus appears (Gap), simultaneously to its appearance (Baseline), or with peripheral stimulus offset (Overlap). The data from the experimental conditions showed the expected pattern, with average latencies being the shortest in the Gap and longest in the Overlap condition. Females were faster (p = .004) than males in the Gap condition, which could indicate that arousal-related effects differ as a function of biological sex. Infants from higher SES were slower (p = .031) in the Overlap condition compared to lower SES infants. This suggests that basic visual attention may differ by socio-cultural background, and should be considered when studying visual attention and its developmental correlates. We observed no significant association to concurrent developmental level or adaptive function. Given its large sample size, this study provides a useful reference for future studies of visual disengagement in early infancy.

Agnieszka Gidziela, Kaili Rimfeld, Margherita Malanchini, Andrea G. Allegrini, Andrew McMillan, Saskia Selzam, Angelica Ronald, Essi Viding, Sophie Stumm, Thalia C. Eley, Robert Plomin (2022)Using DNA to predict behaviour problems from preschool to adulthood, In: Journal of child psychology and psychiatry63(7)pp. 781-792

Background One goal of the DNA revolution is to predict problems in order to prevent them. We tested here if the prediction of behaviour problems from genome‐wide polygenic scores (GPS) can be improved by creating composites across ages and across raters and by using a multi‐GPS approach that includes GPS for adult psychiatric disorders as well as for childhood behaviour problems. Method Our sample included 3,065 genotyped unrelated individuals from the Twins Early Development Study who were assessed longitudinally for hyperactivity, conduct, emotional problems, and peer problems as rated by parents, teachers, and children themselves. GPS created from 15 genome‐wide association studies were used separately and jointly to test the prediction of behaviour problems composites (general behaviour problems, externalising, and internalising) across ages (from age 2 to 21) and across raters in penalised regression models. Based on the regression weights, we created multi‐trait GPS reflecting the best prediction of behaviour problems. We compared GPS prediction to twin heritability using the same sample and measures. Results Multi‐GPS prediction of behaviour problems increased from

Sebastian Lundström, Claire M A Haworth, Eva Carlström, Christopher Gillberg, Jonathan Mill, Maria Råstam, Christina M Hultman, Angelica Ronald, Henrik Anckarsäter, Robert Plomin, Paul Lichtenstein, Abraham Reichenberg, (2010)Trajectories leading to autism spectrum disorders are affected by paternal age: findings from two nationally representative twin studies, In: Journal of child psychology and psychiatry51(7)pp. 850-856

Background: Despite extensive efforts, the causes of autism remain unknown. Advancing paternal age has been associated with various neurodevelopmental disorders. We aim to investigate three unresolved questions: (a) What is the association between paternal age and autism spectrum disorders (ASD)?; (b) Does paternal age moderate the genetic and environmental etiological factors for ASD? (c) Does paternal age affect normal variation in autistic-like traits? Methods: Two nationally representative twin studies from Sweden (n = 11, 122, assessed at age 9 or 12) and the UK (n = 13, 524, assessed at age 9) were used. Categorical and continuous measures of ASD, autistic-like traits and autistic similarity were calculated and compared over paternal age categories. Results: Both cohorts showed a strong association between paternal age and the risk for ASD. A U-shaped risk association could be discerned since the offspring of both the youngest and oldest fathers showed an elevation in the risk for ASD. Autistic similarity increased with advancing paternal age in both monozygotic and dizygotic twins. Both cohorts showed significantly higher autistic-like traits in the offspring of the youngest and oldest fathers. Conclusions: Phenomena associated with paternal age are clearly involved in the trajectories leading to autistic-like traits and ASD. Mechanisms influencing the trajectories might differ between older and younger fathers. Molecular genetic studies are now needed in order to further understand the association between paternal age and ASD, as well as normal variation in social, language, and repetitive behaviors in the general population.

Francesca Happé, Angelica Ronald, Robert Plomin (2006)Time to give up on a single explanation for autism, In: Nature neuroscience9(10)pp. 1218-1220
Angelica Ronald (2014)The times they are a-changin, In: Psychologist (London, England : 1988)27(3)pp. 164-166 British Psychological Soc

Most of the time we think about clinical conditions, such as autism or ADHD or schizophrenia or depression, individually. Yet in reality it is extremely common for people to show more than one condition together. An example is autism and ADHD, which often occur together. The causes for this 'comorbidity have been researched over the last five years, and some startling results are emerging.

Sven Bolte, Charlotte Willfors, Steve Berggren, Joakim Norberg, Lina Poltrago, Katell Mevel, Christina Coco, Peter Fransson, Jacqueline Borg, Rouslan Sitnikov, Roberto Toro, Kristiina Tammimies, Britt-Marie Anderlid, Ann Nordgren, Anna Falk, Urs Meyer, Juha Kere, Mikael Landen, Christina Dalman, Angelica Ronald, Henrik Anckarsater, Paul Lichtenstein (2014)The Roots of Autism and ADHD Twin Study in Sweden (RATSS), In: Twin research and human genetics17(3)pp. 164-176 Cambridge Univ Press

Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.

Sara Moruzzi, Anna Ogliari, Angelica Ronald, Francesca Happe, Marco Battaglia (2011)The Nature of Covariation Between Autistic Traits and Clumsiness: A Twin Study in a General Population Sample, In: Journal of autism and developmental disorders41(12)pp. 1665-1674 Springer Nature

While social impairment, difficulties with communication, and restricted repetitive behaviors are central features of Autism Spectrum Disorders, physical clumsiness is a commonly co-occuring feature. In a sample of 398 twin pairs (aged 8-17 years) from the Italian Twin Registry we investigated the nature of the co-variation between a psychometric index of Clumsiness and the Child Behavior Checklist (CBCL) Autistic scale. Bivariate twin analyses showed that a genetic etiological overlap, rather than direct causation, is a plausible explanation for the association between clumsiness and autistic-like traits, as measured by indices derived from the parent-rated CBCL scale. Additive genetic influences that impinge upon clumsiness/motor problem and autistic-like traits coincided remarkably, with a genetic correlation of 0.63.

Angelica Ronald, Francesca Happé, Robert Plomin (2005)The genetic relationship between individual differences in social and nonsocial behaviours characteristic of autism, In: Developmental science8(5)pp. 444-458 Blackwell Publishing, Ltd
Rebecca Pinto, Fruhling Rijsdijk, Angelica Ronald, Philip Asherson, Jonna Kuntsi (2016)The Genetic Overlap of Attention-Deficit/Hyperactivity Disorder and Autistic-like Traits: an Investigation of Individual Symptom Scales and Cognitive markers, In: Journal of abnormal child psychology44(2)pp. 335-345 Springer Nature

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) frequently co-occur. However, due to previous exclusionary diagnostic criteria, little is known about the underlying causes of this covariation. Twin studies assessing ADHD symptoms and autistic-like traits (ALTs) suggest substantial genetic overlap, but have largely failed to take into account the genetic heterogeneity of symptom subscales. This study aimed to clarify the phenotypic and genetic relations between ADHD and ASD by distinguishing between symptom subscales that characterise the two disorders. Moreover, we aimed to investigate whether ADHD-related cognitive impairments show a relationship with ALT symptom subscales; and whether potential shared cognitive impairments underlie the genetic risk shared between the ADHD and ALT symptoms. Multivariate structural equation modelling was conducted on a population-based sample of 1312 twins aged 7-10. Social-communication ALTs correlated moderately with both ADHD symptom domains (phenotypic correlations around 0.30) and showed substantial genetic overlap with both inattention and hyperactivity-impulsivity (genetic correlation = 0.52 and 0.44, respectively). In addition to previously reported associations with ADHD traits, reaction time variability (RTV) showed significant phenotypic (0.18) and genetic (0.32) association with social-communication ALTs. RTV captured a significant proportion (24 %) of the genetic influences shared between inattention and social-communication ALTs. Our findings suggest that social-communication ALTs underlie the previously observed phenotypic and genetic covariation between ALTs and ADHD symptoms. RTV is not specific to ADHD symptoms, but is also associated with social-communication ALTs and can, in part, contribute to an explanation of the co-occurrence of ASD and ADHD.

Francesca Happe, Angelica Ronald (2008)The 'Fractionable Autism Triad': A Review of Evidence from Behavioural, Genetic, Cognitive and Neural Research, In: Neuropsychology review18(4)pp. 287-304 Springer Nature

Autism is diagnosed on the basis of a triad of impairments in social interaction, communication, and flexible imaginative functions (with restricted and repetitive behaviors and interests; RRBIs). There has been a strong presumption that these different features of the syndrome are strongly intertwined and proceed from a common cause at the genetic, cognitive and neural levels. In this review we examine evidence for an alternative approach, considering the triad as lamely 'fractionable'. We present evidence from Our own twin Studies, and review relevant literature on autism and autistic-like traits in other groups. We Suggest that largely independent genes may operate on social skills/impairments, communication abilities, and RRBIs, requiring a change in molecular-genetic research approaches. At the cognitive level, we suggest that satisfactory accounts exist for each of the triad domains, but no single unitary account can explain both social and nonsocial features of autism. We discuss the implications of the fractionable-triad approach for both diagnosis and future research directions.

Parent ratings of behavior problems in childhood show substantial genetic influence and modest shared environmental influence. However, few studies have compared these results to teacher ratings and no previous studies have compared same-teacher ratings to different-teacher ratings. 3,714 7-year-old twin pairs in the Twins Early Development Study were rated by parents and teachers on the Strengths and Difficulties Questionnaire. Substantial heritability and negligible shared environmental influence were found for data from all three raters for total behavior problems, hyperactivity, prosocial behavior, peer problems, conduct problems, and emotional symptoms. Sex-limitation models revealed similar results for males and females, although there was some evidence for greater heritability for boys, especially when twins were rated by the same teacher.

Terje Falck-Ytter, Linnea Hamrefors, Monica Siqueiros Sanches, Ana Maria Portugal, Mark Taylor, Danyang Li, Charlotte Viktorsson, Irzam Hardiansyah, Lynnea Myers, Lars Westberg, Sven Bölte, Kristiina Tammimies, Angelica Ronald, (2021)The Babytwins Study Sweden (BATSS): A Multi-Method Infant Twin Study of Genetic and Environmental Factors Influencing Infant Brain and Behavioral Development, In: Twin research and human genetics24(4)pp. 217-227 Cambridge University Press

Twin studies can help us understand the relative contributions of genes and environment to phenotypic trait variation, including attentional and brain activation measures. In terms of applying methodologies such as electroencephalography (EEG) and eye tracking, which are key methods in developmental neuroscience, infant twin studies are almost nonexistent. Here, we describe the Babytwins Study Sweden (BATSS), a multi-method longitudinal twin study of 177 MZ and 134 DZ twin pairs (i.e., 622 individual infants) covering the 5−36 month time period. The study includes EEG, eye tracking and genetics, together with more traditional measures based on in-person testing, direct observation and questionnaires. The results show that interest in participation in research among twin parents is high, despite the comprehensive protocol. DNA analysis from saliva samples was possible in virtually all participants, allowing for both zygosity confirmation and polygenic score analyses. Combining a longitudinal twin design with advanced technologies in developmental cognitive neuroscience and genomics, BATSS represents a new approach in infancy research, which we hope to have impact across multiple disciplines in the coming years.

Sania Shakoor, Helena M S Zavos, Alice M Gregory, Angelica Ronald (2021)The association between bullying-victimisation and sleep disturbances in adolescence: Evidence from a twin study, In: Journal of sleep research30(5)pp. e13321-n/a

Bullying-victimisation has been associated with sleep disturbances. This study investigated the degree to which subtypes of bullying-victimisation in adolescence are linked with sleep disturbances. Genetic and environmental contributions underlying bullying-victimisation and sleep disturbances were investigated. Participants (3,242-5,076 pairs) from a longitudinal community twin study reported on their bullying-victimisation at the age of 14 years, and sleep quality and insomnia symptoms at age 16. Regression analyses were used, accounting for the role of individual and family factors. Structural equation twin model fitting was conducted. Bullying-victimisation was modestly associated with sleep quality and insomnia symptoms (r = 0.22-0.23) and a similar strength of associations was found across bullying-victimisation subtypes (r = 0.11-0.22). Bullying-victimisation, sleep quality and insomnia symptoms were predominantly influenced by genes (25-59%) and non-shared environments (40-62%). The association between bullying-victimisation and sleep quality was explained by genetic and non-shared environmental influences. For insomnia symptoms and sleep quality, the association with bullying-victimisation was in part explained by a genetic overlap. Associations between bullying-victimisation and sleep disturbances are not limited to specific aspects of bullying-victimisation but appear to exist for all subtypes. These findings stimulate research questions regarding the mechanisms underlying these links. For example, could certain heritable traits, such as temperament, increase vulnerability to experiencing sleep disturbances and being bullied? Research on bullying and sleep should aim to take the role of genetic predisposition into account, while also noting that it is not the only causal influence. Understanding more about these pathways could strengthen the development of techniques to prevent these difficulties from occurring.

Angelica Ronald, Frank M. Spinath, Robert Plomin (2002)The Aetiology of High Cognitive Ability in Early Childhood, In: High ability studies13(2)pp. 103-114 Taylor & Francis Group

Both the environment and genetics are likely to influence the development of cognitive talent during the preschool years. It is not known to what degree or how these influences differ from those throughout the range of ability. 1943 twin pairs were assessed at 2, 3 and 4 years of age using diverse verbal and nonverbal cognitive measures. Consistently high scoring children were selected on a general cognitive factor. From behavioural genetic model fitting analyses, substantial shared environmental (70%) and modest genetic influences (20%) were found in the high group and this matched the aetiology of the entire sample. Strong genetic predisposition was not apparent. Individual differences in cognitive ability and high ability is largely due to shared environment during the preschool years.

Salvador SOTO-FARACO, Angelica Ronald, Charles Spence (2004)Tactile selective attention and body posture: Assessing the multisensory contributions of vision and proprioception, In: Perception & psychophysics66(7)pp. 1077-1094 Psychonomic Society
Angelica Ronald, Nora de Bode, Tinca J.C. Polderman (2021)Systematic Review: How the Attention-Deficit/Hyperactivity Disorder Polygenic Risk Score Adds to Our Understanding of ADHD and Associated Traits, In: Journal of the American Academy of Child and Adolescent Psychiatry60(10)pp. 1234-1277 Elsevier Inc

To investigate, by systematically reviewing the literature, whether the attention-deficit/hyperactivity disorder (ADHD) polygenic risk score (PRS) associates with ADHD and related traits in independent clinical and population samples. PubMed, Embase and PsychoInfo were systematically searched, alongside study bibliographies. Quality assessments were conducted, and a best-evidence synthesis was applied. Studies were excluded when the predictor was not based on the latest ADHD genome-wide association study, when PRS was not based on genome-wide results, or when the study was a review. Initially, 197 studies were retrieved (February 22, 2020), and a second search (June 3, 2020) yielded a further 49 studies. From both searches, 57 studies were eligible, and 44 studies met inclusion criteria. Included studies were published in the last 3 years. Over 80% of the studies were rated excellent, based on a standardized quality assessment. Evidence of associations between ADHD PRS and the following categories was strong: ADHD, ADHD traits, brain structure, education, externalizing behaviors, neuropsychological constructs, physical health, and socioeconomic status. Evidence for associations with addiction, autism, and mental health were mixed and were, so far, inconclusive. Odds ratios for PRS associating with ADHD ranged from 1.22% to 1.76%; variance explained in dimensional assessments of ADHD traits was 0.7% to 3.3%. A new wave of high-quality research using the ADHD PRS has emerged. Eventually, symptoms may be partly identified based on PRS, but the current ADHD PRS is useful for research purposes only. This review shows that the ADHD PRS is robust and reliable, associating not only with ADHD but many outcomes and challenges known to be linked to ADHD. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects approximately 5% of children and 2.5% of adults.1 Decades of past research have established the significant twin heritability of ADHD and family studies demonstrate its high familiality.2,3 More recently, significant single nucleotide polymorphism (SNP) heritability estimates for ADHD have been reported.4 Together this evidence supports the hypothesis that common genetic variants acting additively play a role in the causes of ADHD.3 In addition, twin, family, and molecular genetic studies suggest that these common variants may, to some degree, be shared with other conditions and traits, including autism and autistic traits,5-10 tobacco and alcohol use,11,12 and depressive and hypomanic symptoms.13-15

Angelica Ronald, Henrik Larsson, Henrik Anckarsäter, Paul Lichtenstein, (2014)Symptoms of autism and ADHD: a Swedish twin study examining their overlap, In: Journal of abnormal psychology (1965)123(2)pp. 440-451

Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) show high comorbidity. The following questions were addressed regarding their specific symptoms: What is the factor structure of ASD and ADHD symptoms, to what degree do different symptom domains cluster together, to what extent are these domains caused by the same genetic and environmental influences, and what is the best model of their co-occurrence? A population-based twin cohort of over 17,000 9- and 12-year-olds were assessed using the Autism-Tics, AD/HD, and other Comorbidities parental interview inventory. Principal component analyses were conducted, and symptom domain clustering was assessed. Four multivariate twin models were compared. Factors split into three ASD (social impairments, communication impairments, and restricted repetitive behaviors and interests), and three ADHD (inattention, hyperactivity, and impulsivity) symptom domains. Some ASD-ADHD symptom domain combinations clustered together often, although others not at all. A two-factor common pathway model fit the data, suggesting that ASD and ADHD symptom domains tap into separate "ASD" and "ADHD" latent factors that showed high genetic overlap. All subdomains also showed significant specific genetic and environmental influences, reflecting the etiological heterogeneity both within and between ASD and ADHD. These findings support the conceptual distinction of ASD and ADHD, and demonstrate the considerable natural co-occurrence of particular ASD/ADHD symptom domains. The results imply that more children with 1 condition show features of the other condition than show complete comorbidity. Emphasis on symptom co-occurrence, rather than complete comorbidity between disorders, may help focus clinical approaches and advance molecular genetic research.

Frank M Spinath, Nicole Harlaar, Angelica Ronald, Robert Plomin (2004)Substantial genetic influence on mild mental impairment in early childhood, In: American journal of mental retardation109(1)pp. 34-43

We report the first major genetic study of mild mental impairment. From a representative sample of 3886 twins (1314 monozygotic, 1296 dizygotic same-sex, and 1276 dizygotic opposite-sex), the lowest 5% were selected on a composite measure of verbal and nonverbal abilities assessed by parents when the twins were 2, 3, and 4 years of age. Twin concordances for mild mental impairment were 74% for monozygotic twins, 45% for same-sex, and 36% for opposite-sex dizygotic twins, indicating substantial genetic influence. Model-fitting analyses estimated group heritability as.49, which is significantly greater than heritability for the rest of the population in early childhood. These results suggest that mild mental impairment is a good target for neuroscience research on global brain function and dysfunction.

Karla Holmboe, Fruhling V. Rijsdijk, Victoria Hallett, Francesca Happe, Robert Plomin, Angelica Ronald (2014)Strong Genetic Influences on the Stabiliiy of Autistic Traits in Childhood, In: Journal of the American Academy of Child and Adolescent Psychiatry53(2)pp. 221-230 Elsevier

Objective: Disorders on the autism spectrum, as well as autistic traits in the general population, have been found to be both highly stable across age and highly heritable at individual ages. However, little is known about the overlap in genetic and environmental influences on autistic traits across age and the contribution of such influences to trait stability itself. The present study investigated these questions in a general population sample of twins. Method: More than 6,000 twin pairs were rated on an established scale of autistic traits by their parents at 8, 9, and 12 years of age and by their teachers at 9 and 12 years of age. Data were analyzed using structural equation modeling. Results: The results indicated that, consistently across raters, not only were autistic traits stable, and moderately to highly heritable at individual ages, but there was also a high degree of overlap in genetic influences across age. Furthermore, autistic trait stability could largely be accounted for by genetic factors, with the environment unique to each twin playing a minor role. The environment shared by twins had virtually no effect on the longitudinal stability in autistic traits. Conclusions: Autistic traits are highly stable across middle childhood, and this stability is caused primarily by genetic factors.

Juan J. Madrid-Valero, Angelica Ronald, Nicholas Shakeshaft, Kerry Schofield, Margherita Malanchini, Alice M. Gregory (2020)Sleep quality, insomnia, and internalizing difficulties in adolescents: insights from a twin study, In: Sleep (New York, N.Y.)43(2) Oxford Univ Press

Study Objectives: There is a well-established association between poor sleep quality and internalizing traits. This relationship has previously been studied using a twin design. However, when it comes to adolescence, there is a paucity of twin studies that have investigated this relationship, despite the importance of this developmental stage for both the development of poor sleep quality and internalizing symptoms. Additionally, anxiety sensitivity, which is commonly associated with poor sleep quality, has not been studied in this context. Our objective was to estimate genetic and environmental influences on the relationships between insomnia, poor sleep quality, and internalizing symptoms in adolescence. Methods: Insomnia, poor sleep quality, depression, anxiety, and anxiety sensitivity traits were measured in a sample of 5111 twin pairs from the Twins Early Development Study, born between 1994 and 1996 (mean age 16.32 years [SD = 0.68]). Results: A moderate proportion of the variance for the different variables (.29-.42) was explained by genetic factors. Associations between sleep and internalizing variables were moderate (r =.34-.46) and there was a large genetic overlap between these variables (rA=.51-.73). Conclusion: This study adds novel information by showing that there are large genetic correlations between sleep disturbances and internalizing symptoms in adolescence.

Evie Stergiakouli, George Davey Smith, Joanna Martin, David H Skuse, Wolfgang Viechtbauer, Susan M Ring, Angelica Ronald, David E Evans, Simon E Fisher, Anita Thapar, Beate St Pourcain (2017)Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development, In: Molecular autism8(1)pp. 1-13

Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. Social-communication difficulties (  ≤ 5551, Social and Communication Disorders Checklist, SCDC) and combined hyperactive-impulsive/inattentive ADHD symptoms (  ≤ 5678, Strengths and Difficulties Questionnaire, SDQ-ADHD) were repeatedly measured in a UK birth cohort (ALSPAC, age 7 to 17 years). Genome-wide summary statistics on clinical ASD (5305 cases; 5305 pseudo-controls) and ADHD (4163 cases; 12,040 controls/pseudo-controls) were available from the Psychiatric Genomics Consortium. Genetic trait variances and genetic overlap between phenotypes were estimated using genome-wide data. In the general population, genetic influences for SCDC and SDQ-ADHD scores were shared throughout development. Genetic correlations across traits reached a similar strength and magnitude (cross-trait  ≤ 1,    3 × 10 ) as those between repeated measures of the same trait (within-trait  ≤ 0.94,    7 × 10 ). Shared genetic influences between traits, especially during later adolescence, may implicate variants in K-RAS signalling upregulated genes ( -meta = 6.4 × 10 ). Uni-dimensionally, each population-based trait mapped to the expected behavioural continuum: risk-increasing alleles for clinical ADHD were persistently associated with SDQ-ADHD scores throughout development (marginal regression  = 0.084%). An age-specific genetic overlap between clinical ASD and social-communication difficulties during childhood was also shown, as per previous reports. Cross-dimensionally, however, neither SCDC nor SDQ-ADHD scores were linked to genetic risk for disorder. In the general population, genetic aetiologies between social-communication difficulties and ADHD symptoms are shared throughout child and adolescent development and may implicate similar biological pathways that co-vary during development. Within both the ASD and the ADHD dimension, population-based traits are also linked to clinical disorder, although much larger clinical discovery samples are required to reliably detect cross-dimensional trait-disorder relationships.

Helena M. S. Zavos, Thalia C. Eley, Philip McGuire, Robert Plomin, Alastair G. Cardno, Daniel Freeman, Angelica Ronald (2016)Shared Etiology of Psychotic Experiences and Depressive Symptoms in Adolescence: A Longitudinal Twin Study, In: Schizophrenia bulletin42(5)pp. 1197-1206 Oxford Univ Press

Psychotic disorders and major depression, both typically adult-onset conditions, often co-occur. At younger ages psychotic experiences and depressive symptoms are often reported in the community. We used a genetically sensitive longitudinal design to investigate the relationship between psychotic experiences and depressive symptoms in adolescence. A representative community sample of twins from England and Wales was employed. Self-rated depressive symptoms, paranoia, hallucinations, cognitive disorganization, grandiosity, anhedonia, and parent-rated negative symptoms were collected when the twins were age 16 (N = 9618) and again on a representative subsample 9 months later (N = 2873). Direction and aetiology of associations were assessed using genetically informative cross-lagged models. Depressive symptoms were moderately correlated with paranoia, hallucinations, and cognitive disorganization. Lower correlations were observed between depression and anhedonia, and depression and parent-rated negative symptoms. Nonsignificant correlations were observed between depression and grandiosity. Largely the same genetic effects influenced depression and paranoia, depression and hallucinations, and depression and cognitive disorganization. Modest overlap in environmental influences also played a role in the associations. Significant bidirectional longitudinal associations were observed between depression and paranoia. Hallucinations and cognitive disorganization during adolescence were found to impact later depression, even after controlling for earlier levels of depression. Our study shows that psychotic experiences and depression, as traits in the community, have a high genetic overlap in mid-adolescence. Future research should test the prediction stemming from our longitudinal results, namely that reducing or ameliorating positive and cognitive psychotic experiences in adolescence would decrease later depressive symptoms.

Ayden Saffari, Matt Arno, Eric Nasser, Angelica Ronald, Chloe C Y Wong, Leonard C Schalkwyk, Jonathan Mill, Frank Dudbridge, Emma L Meaburn (2019)RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation, In: Molecular autism10(1)pp. 38-38

A gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC. Genome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (  = 36) and (b) within discordant ASC MZ twin pairs (total  = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in . In the discordant twin analysis, three genes showed evidence for DE at FDR 

Angelica Ronald, Lee M. Butcher, Sophia J. Docherty, Oliver S. P. Davis, Leonard C. Schalkwyk, Ian W. Craig, Robert Plomin (2010)Response to comment by Stuart Macgregor, In: Behavior genetics40(1)pp. 48-48 Springer US
Katharina Dworzynski, Francesca Happe, Patrick Bolton, Angelica Ronald (2009)Relationship Between Symptom Domains in Autism Spectrum Disorders: A Population Based Twin Study, In: Journal of autism and developmental disorders39(8)pp. 1197-1210 Springer Nature

Factor structure and relationship between core features of autism (social impairments, communication difficulties, and restricted, repetitive behaviours or interests (RRBIs)) were explored in 189 children from the Twins Early Development Study, diagnosed with autistic spectrum disorders (ASDs) using the Development and Wellbeing Assessment (DAWBA; Goodman et al. in J Child Psychol Psyc 41:645-655, 2000). A bottom-up approach (analysis 1) used principal component factor analysis of DAWBA items indicating five factors, the first three mapping on the triad. In analysis 2, applying top-down DSM-IV criteria, correlations between domains were modest, strongest between social and communication difficulties. Cross-twin cross-trait correlations suggested small shared genetic effects between RRBIs and other symptoms. These findings from a clinical sample of twins indicate a fractionation of social/communicative and RRBI symptoms in ASD.

Pedro M. Vital, Angelica Ronald, Gregory L. Wallace, Francesca Happe (2009)Relationship between special abilities and autistic-like traits in a large population-based sample of 8-year-olds, In: Journal of child psychology and psychiatry50(9)pp. 1093-1101 Wiley

Background: The raised incidence of special abilities or 'savant skills' among individuals with autism spectrum disorders (ASD) relative to other developmental disorders suggests an association between the traits characteristic of ASD and special abilities. The purpose of this study was to investigate the association between special abilities and ASD-like traits. Methods: This study compared the scores of 6,426 8-year-olds with and without parent-reported special abilities on a screening questionnaire for ASD-like traits in three areas: social interaction, communication, and restricted and repetitive behaviours and interests. Measures of IQ, sex, and socioeconomic status (SES) were also compared. Results: From parent report, children with special abilities showed significantly more ASD-like traits than those without such abilities. General intelligence did not mediate this relationship: IQ was found to be positively associated with ability, but negatively associated with ASD-like traits. Special abilities were more strongly associated with restricted/repetitive characteristics than with social or communication traits. Conclusions: Results support the association between special abilities and ASD-like traits, and expand it to traits in the general population. The type of nonsocial traits most strongly associated with parental reports of special abilities suggests a link to a featural information processing style, or 'weak central coherence'.

Jonathan Mill, Xiaohui Xu, Angelica Ronald, Sarah Curran, Tom Price, Jo Knight, Ian Craig, Pak Sham, Robert Plomin, Philip Asherson (2005)Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B, In: American journal of medical genetics. Part B, Neuropsychiatric genetics133B(1)pp. 68-73 Wiley Subscription Services, Inc., A Wiley Company
Ana Maria Portugal, Mark J. Taylor, Charlotte Viktorsson, Pär Nyström, Danyang Li, Kristiina Tammimies, Angelica Ronald, Terje Falck-Ytter (2022)Pupil size and pupillary light reflex in early infancy: heritability and link to genetic liability to schizophrenia, In: Journal of child psychology and psychiatry63(9)pp. 1068-1077

Background Measures based on pupillometry, such as the pupillary light reflex (PLR) and baseline pupil size, reflect physiological responses linked to specific neural circuits that have been implicated as atypical in some psychiatric and neurodevelopmental conditions. Methods We investigated the contribution of genetic and environmental factors to the baseline pupil size and the PLR in 510 infant twins assessed at 5 months of age (281 monozygotic and 229 dizygotic pairs), and its associations with common genetic variants associated with neurodevelopmental (autism spectrum disorder and attention deficit hyperactivity disorder) and mental health (bipolar disorder, major depressive disorder and schizophrenia) conditions using genome‐wide polygenic scores (GPSs). Results Univariate twin modelling showed high heritability at 5 months for both pupil size (h2 = .64) and constriction in response to light (h2 = .62), and bivariate twin modeling indicated substantial independence between the genetic factors influencing each (rG = .38). A statistically significant positive association between infant tonic pupil size and the GPS for schizophrenia was found (β = .15, p = .024), while there was no significant association with the GPS for autism or any other GPSs. Conclusions This study shows that some pupil measures are highly heritable in early infancy, although substantially independent in their genetic etiologies, and associated with common genetic variants linked to schizophrenia. It illustrates how genetically informed studies of infants may help us understand early physiological responses associated with psychiatric disorders which emerge much later in life.

Anja Hollowell, Angelica Ronald (2020)Psychotic experiences associate with a Bias Against Disconfirmatory Evidence (BADE) in adolescence, In: Schizophrenia research218pp. 304-305 Elsevier
Sania Shakoor, Helena M. S. Zavos, Philip McGuire, Alastair G. Cardno, Daniel Freeman, Angelica Ronald (2015)Psychotic experiences are linked to cannabis use in adolescents in the community because of common underlying environmental risk factors, In: Psychiatry research227(2-3)pp. 144-151 Elsevier

Cannabis users are more likely to have psychotic experiences (PEs). The degree to which these associations are driven by genetic or environmental influences in adolescence is unknown. This study estimated the genetic and environmental contributions to the relationship between cannabis use and PEs. Specific PEs were measured in a community-based twin sample (4830 16-year-old pairs) using self-reports and parent-reports. Adolescents reported on ever using cannabis. Multivariate liability threshold structural equation model-fitting was conducted. Cannabis use was significantly correlated with PEs. Modest heritability (37%), common environmental influences (55%) and unique environment (8%) were found for cannabis use. For PEs, modest heritability (27-.54%), unique environmental influences (E=12-50%) and little common environmental influences (11-20%), with the exception of parent-rated Negative Symptoms (42%), were reported. Environmental influences explained all of the covariation between cannabis us and paranoia, cognitive disorganization and parent-rated negative symptoms (bivariate common environment=69-100%, bivariate unique environment=28-31%), whilst the relationship between cannabis use and hallucinations indicated familial influences. Cannabis use explains 2-5% of variance in positive, cognitive, and negative PEs. Cannabis use and psychotic experience co-occur due to environmental factors. Focus on specific environments may reveal why adolescent cannabis use and psychotic experiences tend to 'travel together'. (C) 2015 The Authors. Puhlished by Elsevier Ireland Ltd. This is an open access article under the CC BY license (

Angelica Ronald, Craig E. Pennell, Andrew J. O. Whitehouse (2011)Prenatal maternal stress associated with ADHD and autistic traits in early childhood, In: Frontiers in psychology2pp. 223-223 Frontiers Media Sa

Research suggests that offspring of mothers who experience high levels of stress during pregnancy are more likely to have problems in neurobehavioral development. There is preliminary evidence that prenatal maternal stress (PNMS) is a risk factor for both autism and attention deficit hyperactivity disorder (ADHD), however most studies do not control for confounding factors and no study has investigated PNMS as a risk factor for behaviors characteristic of these disorders in early childhood. A population cohort of 2900 pregnant women were recruited before their 18th week of pregnancy and investigated prospectively. Maternal experience of stressful life events was assessed during pregnancy. When offspring were age 2 years, mothers completed the child behavior checklist. Multiple regression showed that maternal stressful events during pregnancy significantly predicted ADHD behaviors in offspring, after controlling for autistic traits and other confounding variables, in both males (p = 0.03) and females (p = 0.01). Similarly, stressful events during pregnancy significantly predicted autistic traits in the offspring after controlling for ADHD behaviors and confounding variables, in males only (p = 0.04). In conclusion, this study suggests that PNMS, in the form of typical stressful life events such as divorce or a residential move, show a small but significant association with both autistic traits and ADHD behaviors independently, in offspring at age 2 years, after controlling for multiple antenatal, obstetric, postnatal, and sociodemographic covariates. This finding supports future research using epigenetic, cross-fostering, and gene-environment interaction designs to identify the causal processes underlying this association.

Charlotte Viktorsson, Ana Maria Portugal, Danyang Li, Maja Rudling, Monica Siqueiros Sanchez, Kristiina Tammimies, Mark J. Taylor, Angelica Ronald, Terje Falck-Ytter (2023)Preferential looking to eyes versus mouth in early infancy: heritability and link to concurrent and later development, In: Journal of child psychology and psychiatry64(2)pp. 311-319

Background From birth, infants orient preferentially to faces, and when looking at the face, they attend primarily to eyes and mouth. These areas convey different types of information, and earlier research suggests that genetic factors influence the preference for one or the other in young children. Methods In a sample of 535 5‐month‐old infant twins, we assessed eye (relative to mouth) preference in early infancy, i.e., before neural systems for social communication and language are fully developed. We investigated the contribution of genetic and environmental factors to the preference for looking at eyes, and the association with concurrent traits and follow‐up measures. Results Eye preference was independent from all other concurrent traits measured, and had a moderate‐to‐high contribution from genetic influences (A = 0.57; 95% CI: 0.45, 0.66). Preference for eyes at 5 months was associated with higher parent ratings of receptive vocabulary at 14 months. No statistically significant association with later autistic traits was found. Preference for eyes was strikingly stable across different stimulus types (e.g., dynamic vs. still), suggesting that infants' preference at this age does not reflect sensitivity to low‐level visual cues. Conclusions These results suggest that individual differences in infants' preferential looking to eyes versus mouth to a substantial degree reflect genetic variation. The findings provide new leads on both the perceptual basis and the developmental consequences of these attentional biases.

Angelica Ronald, Francesca Happé, Thomas S Price, Simon Baron-Cohen, Robert Plomin (2006)Phenotypic and genetic overlap between autistic traits at the extremes of the general population, In: Journal of the American Academy of Child and Adolescent Psychiatry45(10)pp. 1206-1214

To investigate children selected from a community sample for showing extreme autistic-like traits and to assess the degree to which these individual traits--social impairments (SIs), communication impairments (CIs), and restricted repetitive behaviors and interests (RRBIs)--are caused by genes and environments, whether all of them are caused by the same genes and environments, and how often they occur together (as required by an autism diagnosis). The most extreme-scoring 5% were selected from 3,419 8-year-old pairs in the Twins Early Development Study assessed on the Childhood Asperger Syndrome Test. Phenotypic associations between extreme traits were compared with associations among the full-scale scores. Genetic associations between extreme traits were quantified using bivariate DeFries-Fulker extremes analysis. Phenotypic relationships between extreme SIs, CIs, and RRBIs were modest. There was a degree of genetic overlap between them, but also substantial genetic specificity. This first twin study assessing the links between extreme individual autistic-like traits (SIs, CIs, and RRBIs) found that all are highly heritable but show modest phenotypic and genetic overlap. This finding concurs with that of an earlier study from the same cohort that showed that a total autistic symptoms score at the extreme showed high heritability and that SIs, CIs, and RRBIs show weak links in the general population. This new finding has relevance for both clinical models and future molecular genetic studies.

Alice P. Jones, Henrik Larsson, Angelica Ronald, Fruhling Rijsdijk, Patricia Busfield, Andrew Mcmillan, Robert Plomin, Essi Viding (2009)PHENOTYPIC AND AETIOLOGICAL ASSOCIATIONS BETWEEN PSYCHOPATHIC TENDENCIES, AUTISTIC TRAITS, AND EMOTION ATTRIBUTION, In: Criminal justice and behavior36(11)pp. 1198-1212 Sage

Some behavioural overlap exists between psychopathic tendencies and autistic traits, and both phenotypes are thought to be associated with problems in empathy. However, the broad behavioural profiles and the cognitive-affective deficits associated with the two conditions are at least partly separable. The main aim of this study was to assess the extent to which the aetiology of psychopathic tendencies is independent of autistic traits. A secondary aim was to study the aetiology of emotion attribution ability and its association with psychopathic tendencies and autistic traits. Based on data from a sample of 642 twin pairs, the genetic and nonshared environmental influences related to psychopathic tendencies were largely unique to each phenotype. Common environmental influences between psychopathic tendencies and autistic traits overlapped. Poorer emotion attribution ability was associated with increased psychopathic tendencies and autistic traits, and these associations were mainly explained by common genetic factors.

Elizabeth O'Nions, Essi Viding, Corina U. Greven, Angelica Ronald, Francesca Happe (2014)Pathological demand avoidance: Exploring the behavioural profile, In: Autism : the international journal of research and practice18(5)pp. 538-544 Sage

'Pathological Demand Avoidance' is a term increasingly used by practitioners in the United Kingdom. It was coined to describe a profile of obsessive resistance to everyday demands and requests, with a tendency to resort to 'socially manipulative' behaviour, including outrageous or embarrassing acts. Pathological demand avoidance is thought to share aspects of social impairment with autism spectrum disorders, but autism spectrum disorder-appropriate strategies, such as routine and repetition, are described as unhelpful. Outrageous acts and lack of concern for their effects draw parallels with conduct problems and callous-unemotional traits. However, reward-based techniques, effective with conduct problems and callous-unemotional traits, seem not to work in pathological demand avoidance. Despite increasing interest and controversy over the pathological demand avoidance label, there is only one published study to date. We present the first systematic comparison of the behavioural profile of children receiving the term pathological demand avoidance (N = 25) to children with autism spectrum disorders (N = 39) or conduct problems and callous-unemotional traits (N = 28), using parent-report indices of psychopathology. The pathological demand avoidance group displayed comparable levels of autistic traits and peer problems to the autism spectrum disorders group and anti-social traits approaching those seen in the conduct problems and callous-unemotional traits group. Emotional symptoms in pathological demand avoidance exceeded both comparison groups. Findings highlight the extreme behavioural impairment associated with pathological demand avoidance and the need to explore whether behavioural overlap reflects a similar neurocognitive basis to existing groups.

Magdalena Janecka, Claire M.A. Haworth, Angelica Ronald, Eva Krapohl, Francesca Happé, Jonathan Mill, Leonard C. Schalkwyk, Cathy Fernandes, Abraham Reichenberg, Frühling Rijsdijk (2017)Paternal Age Alters Social Development in Offspring, In: Journal of the American Academy of Child and Adolescent Psychiatry56(5)pp. 383-390 Elsevier Inc

Advanced paternal age (APA) at conception has been linked with autism and schizophrenia in offspring, neurodevelopmental disorders that affect social functioning. The current study explored the effects of paternal age on social development in the general population. We used multilevel growth modeling to investigate APA effects on socioemotional development from early childhood until adolescence, as measured by the Strengths and Difficulties Questionnaire (SDQ) in the Twins Early Development Study (TEDS) sample. We also investigated genetic and environmental underpinnings of the paternal age effects on development, using the Additive genetics, Common environment, unique Environment (ACE) and gene–environment (GxE) models. In the general population, both very young and advanced paternal ages were associated with altered trajectory of social development (intercept: p = .01; slope: p = .03). No other behavioral domain was affected by either young or advanced age at fatherhood, suggesting specificity of paternal age effects. Increased importance of genetic factors in social development was recorded in the offspring of older but not very young fathers, suggesting distinct underpinnings of the paternal age effects at these two extremes. Our findings highlight that the APA-related deficits that lead to autism and schizophrenia are likely continuously distributed in the population.

Mark Taylor, Angelica Ronald (2013)Out of the shadow of others, In: Psychologist (London, England : 1988)26(10)pp. 758-759 British Psychological Soc
Fiona McEwen, Francesca Happé, Patrick Bolton, Fruhling Rijsdijk, Angelica Ronald, Katharina Dworzynski, Robert Plomin (2007)Origins of individual differences in imitation: links with language, pretend play, and socially insightful behavior in two-year-old twins, In: Child development78(2)pp. 474-492

Imitation, vocabulary, pretend play, and socially insightful behavior were investigated in 5,206 same- and opposite-sex 2-year-old twin pairs in the United Kingdom. Individual differences in imitative ability were due to modest heritability (30%), while environmental factors shared between twins (42%) and unique to each twin (28%) also made significant contributions to the variance. Imitation correlated significantly, although modestly, with vocabulary, pretend play, and socially insightful behavior, and the strongest relationship was with vocabulary. A model that represented the covariance between the variables as being due to correlated latent genetic and environmental factors fitted the data well, with shared environmental factors influencing most of the covariance. Parents who encourage imitation may also tend to foster the development of language, pretence, and socially insightful behavior.

Charlotte Willfors, Lina Poltrago, Steve Berggren, Christina Coco, Henrik Anckarsäter, Paul Lichtenstein, Angelica Ronald, Sven Bölte, (2014)On the role of non-shared environment for executive functioning in ADHD: a twin-differences design study, In: International journal of developmental disabilities60(3)pp. 163-173 Routledge

Introduction: The study of differences between monozygotic (MZ) twin pairs with respect to ADHD may provide novel leads to disentangle the environmental contribution driving its phenotypes. Objectives: To examine non-shared environmental influences on executive function in dimensionally defined ADHD. Methods: This study included 27 MZ twin pairs (7 female) aged 11-20 years being moderately to substantially discordant for ADHD traits as assessed by the Attention Problem (AP) scale of the Child Behavior Checklist/Adult Behavior Checklist. The twins completed the Wisconsin Card Sorting Test (WCST) for cognitive flexibility and the Tower Test (TT) for foresighted planning. Two statistical approaches were used to analyze the data. First, correlations between ADHD trait intra-pair differences and WCST and TT scores were calculated. Second, the significance of those intra-pair differences on WCST and TT, using ADHD as categorical variable in clinically discordant pairs, was tested. Results: Both analysing strategies revealed a link between ADHD on one hand, and foresighted planning and inhibitory control on the other hand mediated by non-shared environmental factors. The first statistical approach yielded positive correlations between intra-pairs differences on the AP scale and intra-pair differences on two subscales of the TT: total rule violation (r s  = 0·41) and rule-violation-per-item-ratio (r s  = 0·38). Findings in categorically discordant pairs were consistent, showing within-pair differences on the same subtests (z-1·63, P = 0·05, one-tailed and z = −1·60, P = 0·05, one-tailed). Conclusions: Findings confirm previous research suggesting ADHD to be a quantitative extreme on a continuum with executive functions being a cognitive marker of ADHD traits. Non-shared environmental factors appear to influence planning skills and inhibitory control.

Sarah Curran, Katharina Dworzynski, Francesca Happé, Angelica Ronald, Carrie Allison, Simon Baron-Cohen, Carol Brayne, Patrick F Bolton (2011)No major effect of twinning on autistic traits, In: Autism research4(5)pp. 377-382

It has been questioned whether the process of twinning might be a risk factor for autism spectrum conditions (ASC) and autistic traits. We sought to determine whether autistic traits and probable disorder, as measured by the Childhood Autism Spectrum Test (CAST), were more pronounced in twins compared to singletons. Data were analyzed from two large population-based samples of UK children, twins (n = 5,142 twin pairs, aged 8 years) and singletons (n = 2,805, aged 5-9 years). Distributions of CAST scores in both groups were negatively skewed and scores for twins were more variable than singletons. Mean CAST total scores and standard errors (SE) were not significantly different for twins (5.1; SE 0.04) compared to singletons (4.9; SE 0.08). Moreover, contrary to expectations, the likelihood of scoring above the threshold for possible ASC was significantly lower in the twins than the singletons (OR = 0.69; P = 0.002). Subsidiary analyses of CAST scores according to sex, twin type, and subscale scores representing the subdomains of autism found a few significant differences (P

Angelica Ronald, Francesca Happé, Claire Hughes, Robert Plomin (2005)Nice and Nasty Theory of Mind in Preschool Children: Nature and Nurture, In: Social development (Oxford, England)14(4)pp. 664-684 Blackwell Publishing Ltd
Michael S C Thomas, Neil A Forrester, Angelica Ronald (2016)Multiscale Modeling of Gene-Behavior Associations in an Artificial Neural Network Model of Cognitive Development, In: Cognitive science40(1)pp. 51-99

In the multidisciplinary field of developmental cognitive neuroscience, statistical associations between levels of description play an increasingly important role. One example of such associations is the observation of correlations between relatively common gene variants and individual differences in behavior. It is perhaps surprising that such associations can be detected despite the remoteness of these levels of description, and the fact that behavior is the outcome of an extended developmental process involving interaction of the whole organism with a variable environment. Given that they have been detected, how do such associations inform cognitive-level theories? To investigate this question, we employed a multiscale computational model of development, using a sample domain drawn from the field of language acquisition. The model comprised an artificial neural network model of past-tense acquisition trained using the backpropagation learning algorithm, extended to incorporate population modeling and genetic algorithms. It included five levels of description-four internal: genetic, network, neurocomputation, behavior; and one external: environment. Since the mechanistic assumptions of the model were known and its operation was relatively transparent, we could evaluate whether cross-level associations gave an accurate picture of causal processes. We established that associations could be detected between artificial genes and behavioral variation, even under polygenic assumptions of a many-to-one relationship between genes and neurocomputational parameters, and when an experience-dependent developmental process interceded between the action of genes and the emergence of behavior. We evaluated these associations with respect to their specificity (to different behaviors, to function vs. structure), to their developmental stability, and to their replicability, as well as considering issues of missing heritability and gene-environment interactions. We argue that gene-behavior associations can inform cognitive theory with respect to effect size, specificity, and timing. The model demonstrates a means by which researchers can undertake multiscale modeling with respect to cognition and develop highly specific and complex hypotheses across multiple levels of description.

Michael S. C. Thomas, Neil A. Forrester, Angelica Ronald (2013)Modeling Socioeconomic Status Effects on Language Development, In: Developmental psychology49(12)pp. 2325-2343 Amer Psychological Assoc

Socioeconomic status (SES) is an important environmental predictor of language and cognitive development, but the causal pathways by which it operates are unclear. We used a computational model of development to explore the adequacy of manipulations of environmental information to simulate SES effects in English past-tense acquisition, in a data set provided by Bishop (2005). To our knowledge, this is the first application of computational models of development to SES. The simulations addressed 3 new challenges: (a) to combine models of development and individual differences in a single framework, (b) to expand modeling to the population level, and (c) to implement both environmental and genetic/intrinsic sources of individual differences. The model succeeded in capturing the qualitative patterns of regularity effects in both population performance and the predictive power of SES that were observed in the empirical data. The model suggested that the empirical data are best captured by relatively wider variation in learning abilities and relatively narrow variation in (and good quality of) environmental information. There were shortcomings in the model's quantitative fit, which are discussed. The model made several novel predictions, with respect to the influence of SES on delay versus giftedness, the change of SES effects over development, and the influence of SES on children of different ability levels (gene-environment interactions). The first of these predictions was that SES should reliably predict gifted performance in children but not delayed performance, and the prediction was supported by the Bishop data set. Finally, the model demonstrated limits on the inferences that can be drawn about developmental mechanisms on the basis of data from individual differences.

C. C. Y. Wong, E. L. Meaburn, A. Ronald, T. S. Price, A. R. Jeffries, L. C. Schalkwyk, R. Plomin, J. Mill (2014)Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits, In: Molecular psychiatry19(4)pp. 495-503 Springer Nature

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

C Willfors, T Carlsson, B-M Anderlid, A Nordgren, E Kostrzewa, S Berggren, A Ronald, R Kuja-Halkola, K Tammimies, S Bölte (2017)Medical history of discordant twins and environmental etiologies of autism, In: Translational psychiatry7(1)pp. e1014-e1014

The environmental contributions to autism spectrum disorder (ASD) and their informative content for diagnosing the condition are still largely unknown. The objective of this study was to investigate associations between early medical events and ASD, as well as autistic traits, in twins, to test the hypothesis of a cumulative environmental effect on ASD risk. A total of 80 monozygotic (MZ) twin pairs (including a rare sample of 13 twin pairs discordant for clinical ASD) and 46 dizygotic (DZ) twin pairs with varying autistic traits, were examined for intra-pair differences in early medical events (for example, obstetric and neonatal factors, first year infections). First, differences in early medical events were investigated using multisource medical records in pairs qualitatively discordant for ASD. The significant intra-pair differences identified were then tested in relation to autistic traits in the remaining sample of 100 pairs, applying generalized estimating equations analyses. Significant association of the intra-pair differences in the MZ pairs were found for the cumulative load of early medical events and clinical ASD (Z=-2.85, P=0.004) and autistic traits (β=78.18, P=0.002), as well as infant dysregulation (feeding, sleeping abnormalities, excessive crying and worriedness), when controlling for intelligence quotient and attention deficit hyperactivity disorder comorbidity. The cumulative load of early medical events in general, and infant dysregulation in particular, may index children at risk of ASD owing to non-shared environmental contributions. In clinical practice, these findings may facilitate screening and early detection of ASD.

Rosa A. Hoekstra, Francesca Happe, Simon Baron-Cohen, Angelica Ronald (2010)Limited Genetic Covariance Between Autistic Traits and Intelligence: Findings From a Longitudinal Twin Study, In: American journal of medical genetics. Part B, Neuropsychiatric genetics153B(5)pp. 994-1007 Wiley

Intellectual disability is common in individuals with autism spectrum conditions. However, the strength of the association between both conditions and its relevance to finding the underlying (genetic) causes of autism is unclear. This study aimed to investigate the longitudinal association between autistic traits and intelligence in a general population twin sample and to examine the etiology of this association. Parental ratings of autistic traits and performance on intelligence tests were collected in a sample of 8,848 twin pairs when the children were 7/8, 9, and 12 years old. Phenotypic and longitudinal correlations in the sample as a whole were compared to the associations in the most extreme scoring 5% of the population. The genetic and environmental influences on the overlap between autistic traits and IQ and on the stability of this relationship over time were estimated using structural equation modeling. Autistic traits were modestly negatively correlated to intellectual ability, both in the extreme scoring groups and among the full-range scores. The correlation was stable over time and was mainly explained by autistic trait items assessing communication difficulties. Genetic model fitting showed that autistic traits and IQ were influenced by a common set of genes and a common set of environmental influences that continuously affect these traits throughout childhood. The genetic correlation between autistic traits and IQ was only modest. These findings suggest that individual differences in autistic traits are substantially genetically independent of intellectual functioning. The relevance of these findings to future studies is discussed. (C) 2010 Wiley-Liss, Inc.

Mark J. Taylor, Tony Charman, Elise B. Robinson, Marianna E. Hayiou-Thomas, Francesca Happe, Philip S. Dale, Angelica Ronald (2014)Language and Traits of Autism Spectrum Conditions: Evidence of Limited Phenotypic and Etiological Overlap, In: American journal of medical genetics. Part B, Neuropsychiatric genetics165(7)pp. 587-595 Wiley

Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by approximate to 3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation=-0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation=0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier. (c) 2014 Wiley Periodicals, Inc.

Mark J. Taylor, Paul Lichtenstein, Henrik Larsson, Henrik Anckarsäter, Corina U. Greven, Angelica Ronald, (2016)Is There a Female Protective Effect Against Attention-Deficit/Hyperactivity Disorder? Evidence From Two Representative Twin Samples, In: Journal of the American Academy of Child and Adolescent Psychiatry55(6)pp. 504-512.e2 Elsevier Inc

Attention-deficit/hyperactivity disorder (ADHD) is more frequent in males than in females. The “female protective effect” posits that females undergo greater exposure to etiological factors than males in order to develop ADHD, leading to the prediction that relatives of females with ADHD will display more ADHD behaviors. We thus tested whether cotwins of females displaying extreme ADHD traits would display more ADHD traits than cotwins of males displaying extreme ADHD traits. Parents of approximately 7,000 pairs of nonidentical twins in Sweden, and approximately 4,000 pairs of twins in England and Wales, completed dimensional assessments of ADHD traits. Probands were selected on the basis of scoring within the highest 10% of the distribution in each sample. Dimensional scores of cotwins of probands, as well as the categorical recurrence rate, were investigated by proband sex. Cotwins of female probands displayed higher mean ADHD trait scores (mean = 0.62−0.79) than cotwins of male probands (mean = 0.38−0.55) in both samples. This trend was significant in the Swedish sample (p < .01) and when the 2 samples were merged into a single, larger sample (p < .001). When the samples were merged, there was also a significant association between proband sex and cotwin’s categorical status, with more cotwins of female probands also being probands than cotwins of male probands. These findings support a female protective effect against ADHD behaviors, suggesting that females require greater exposure to genetic and environmental factors associated with ADHD in order to develop the condition.

Angelica Ronald (2011)Is the child father of the Man'? Evaluating the stability of genetic influences across development, In: Developmental science14(6)pp. 1471-1478 Wiley

This selective review considers findings in genetic research that have shed light on how genes operate across development. We will address the question of whether the child is father of the Man from a genetic perspective. In other words, do the same genetic influences affect the same traits across development? Using a taster menu approach and prioritizing newer findings on cognitive and behavioral traits, examples from the following genetic disciplines will be discussed: (a) developmental quantitative genetics (such as longitudinal twin studies), (b) neurodevelopmental genetic syndromes with known genetic causes (such as Williams syndrome), (c) developmental candidate gene studies (such as those that link infant and adult populations), (d) developmental genome-wide association studies (GWAS), and (e) DNA resequencing. Evidence presented here suggests that there is considerable genetic stability of cognitive and behavioral traits across development, but there is also evidence for genetic change. Quantitative genetic studies have a long history of assessing genetic continuity and change across development. It is now time for the newer, more technology-enabled fields such as GWAS and DNA resequencing also to take on board the dynamic nature of human behavior.

Simone J. Capp, Jessica Agnew-Blais, Alex Lau-Zhu, Emma Colvert, Charlotte Tye, Umit Aydin, Alexandra Lautarescu, Claire Ellis, Tyler Saunders, Lucy O'Brien, Angelica Ronald, Francesca Happe, Grainne McLoughlin (2022)Is quality of life related to high autistic traits, high ADHD traits and their Interaction? Evidence from a Young-Adult Community-Based twin sample, In: Journal of autism and developmental disorders Springer Nature

This study explored whether high autistic traits, high attention deficit hyperactivity disorder (ADHD) traits and their interaction were associated with quality of life (QoL) in a sample of 556 of young-adult twins (Mean age 22 years 5 months, 52% Female). Four participant groups were created: high autistic traits, high ADHD traits, high autistic/ADHD traits, and low ADHD/autistic traits. High autistic traits were associated with lower QoL across domains (physical, psychological, social, and environmental). High ADHD traits associated with lower physical, psychological, and environmental QoL. The interaction of autistic and ADHD traits was not significant in any domain. While mental health difficulties were associated with lower QoL, after accounting for mental health, most relationships between autistic traits, ADHD traits and QoL remained.

Victoria Hallett, Angelica Ronald, Francesca Happe (2009)Investigating the Association Between Autistic-Like and Internalizing Traits in a Community-Based Twin Sample, In: Journal of the American Academy of Child and Adolescent Psychiatry48(6)pp. 618-627 Elsevier

Objectives: Recent research has suggested that children with autistic spectrum disorders often experience comorbid symptoms of anxiety and depression. However, despite this overlap, no quantitative genetic studies have addressed the phenotypic overlap and the etiologic association between internalizing and autistic-like traits within the general population. This study aimed to investigate the phenotypic and etiologic relation between internalizing and autistic-like traits using a community-based twin sample. Method: We investigated the co-occurrence of these traits in a population-based sample of 3,233 twin pairs aged 8 to 9 years, using both parent- and teacher-report questionnaires. Bivariate structural equation modeling techniques were used to determine the extent to which internalizing and autistic-like traits shared common genetic and environmental influences. Results: Our results showed that there was a modest phenotypic correlation (r = 0.26-0.29) between autistic-like and internalizing traits. The traits were both substantially heritable but were largely independent with regard to their genetic influences (r(G) = 0.12-0.19). Shared environmental influences were modest but were largely common to both traits. Similar results were found using both parent- and teacher reported data. Conclusions: Internalizing and autistic-like traits showed moderate phenotypic overlap within the general population. This association was explained in small part by shared genetic factors, but the results suggested that most genetic influences were specific to either internalizing traits or autistic traits. Given these findings, we discuss the potential mechanisms that may underlie the relation between these traits. J Am. Acad. Child Adolesc. Psychiatry, 2009;48(6):618-627.

Charlotte Viktorsson, Marcus Lindskog, Danyang Li, Kristiina Tammimies, Mark J. Taylor, Angelica Ronald, Terje Falck-Ytter (2022)Infants' sense of approximate numerosity: Heritability and link to other concurrent traits, In: Developmental sciencepp. e13347-e13347 Wiley

The ability to perceive approximate numerosity is present in many animal species, and emerges early in human infants. Later in life, it is moderately heritable and associated with mathematical abilities, but the etiology of the Approximate Number System (ANS) and its degree of independence from other cognitive abilities in infancy is unknown. Here, we assessed the phenotypic specificity as well as the influence of genetic and environmental factors on the ANS in a sample of 5-month-old twins (N = 514). We found a small-to-moderate but statistically significant effect of genetic factors on ANS acuity (heritability = 0.18, 95% CI: 0.02, 0.33), but only when differences in numerosity were relatively large (1:4 ratio). Non-verbal ability assessed with the Mullen Scales of Early Learning (MSEL) was found to be heritable (0.47; 95% CI: 0.34, 0.57) and the phenotypic association between ANS acuity and non-verbal ability performance was close to zero. Similarly, we found no association between ANS acuity and general attention during the task. An unexpected weak but statistically significant negative association between ANS acuity and scores on the receptive language scale of the MSEL was found. These results suggest that early ANS function may be largely independent from other aspects of non-verbal development. Further, variability in ANS in infancy seems to, to some extent, reflect genotypic differences in the population. HighlightsAssessing 514 infant twins with eye tracking, we found that infants' sense of approximate numerosity is heritable and not positively associated with concurrent attentional, cognitive or motor abilities.These results have implications for our understanding of development of mathematical ability and the link between cognitive abilities early in postnatal life.

Angelica Ronald, Essi Viding, Francesca Happé, Robert Plomin (2006)Individual differences in theory of mind ability in middle childhood and links with verbal ability and autistic traits: A twin study, In: Social neuroscience1(3-4)pp. 412-425 Taylor & Francis Group

Identifying the causal processes involved in theory of mind (ToM) development during childhood is an important goal for social neuroscience. This study aimed to investigate, for the first time, the extent to which individual differences in ToM are influenced by genes and environment in middle childhood, and to assess how ToM is linked to autistic-like behaviors and verbal ability. Over 600 9-year-old twin pairs from a subsample of the Twins Early Development Study were assessed on an advanced test of ToM and on verbal ability. Parents, teachers, and the children themselves provided ratings of the twins' autistic traits (social impairments, communication impairments, and restricted repetitive behaviors and interests), using an abbreviated version of the Childhood Asperger Syndrome Test. Autistic traits, particularly communication impairments, significantly predicted ToM performance. Verbal ability showed the strongest phenotypic association with ToM. Twin model-fitting was employed to investigate the causes of this association. Much of the variation in ToM ability and in verbal ability was explained by environmental influences, with modest heritabilities for each, but their association was almost fully explained by shared genetic effects. The possible neural basis underlying this association is discussed.

Kostas A Papageorgiou, Teresa Farroni, Mark H Johnson, Tim J Smith, Angelica Ronald (2015)Individual Differences in Newborn Visual Attention Associate with Temperament and Behavioral Difficulties in Later Childhood, In: Scientific reports5(1)pp. 11264-11264

Recently it was shown that individual differences in attention style in infants are associated with childhood effortful control, surgency, and hyperactivity-inattention. Here we investigated whether effortful control, surgency and behavioral problems in childhood can be predicted even earlier, from individual differences in newborns' average duration of gaze to stimuli. Eighty newborns participated in visual preference and habituation studies. Parents completed questionnaires at follow up (mean age = 7.5 years, SD = 1.0 year). Newborns' average dwell time was negatively associated with childhood surgency (β = -.25, R(2) = .04, p = .02) and total behavioral difficulties (β = -.28, R(2) = .05, p = .04) but not with effortful control (β = .03, R(2) = .001, p = .76). Individual differences in newborn visual attention significantly associated with individual variation in childhood surgency and behavioral problems, showing that some of the factors responsible for this variation are present at birth.

Kostas A. Papageorgiou, Tim J. Smith, Rachel Wu, Mark H. Johnson, Natasha Z. Kirkham, Angelica Ronald (2014)Individual Differences in Infant Fixation Duration Relate to Attention and Behavioral Control in Childhood, In: Psychological science25(7)pp. 1371-1379 Sage

Individual differences in fixation duration are considered a reliable measure of attentional control in adults. However, the degree to which individual differences in fixation duration in infancy (0-12 months) relate to temperament and behavior in childhood is largely unknown. In the present study, data were examined from 120 infants (mean age = 7.69 months, SD = 1.90) who previously participated in an eye-tracking study. At follow-up, parents completed age-appropriate questionnaires about their child's temperament and behavior (mean age of children = 41.59 months, SD = 9.83). Mean fixation duration in infancy was positively associated with effortful control (beta = 0.20, R-2 = .02, p = .04) and negatively with surgency (beta = -0.37, R-2 = .07, p = .003) and hyperactivity-inattention (beta = -0.35, R-2 = .06, p = .005) in childhood. These findings suggest that individual differences in mean fixation duration in infancy are linked to attentional and behavioral control in childhood.

Katharina Dworzynski, Angelica Ronald, Patrick Bolton, Francesca Happe (2012)How Different Are Girls and Boys Above and Below the Diagnostic Threshold for Autism Spectrum Disorders?, In: Journal of the American Academy of Child and Adolescent Psychiatry51(8)pp. 788-797 Elsevier

Objective: This study aimed to explore sex differences in autistic traits in relation to diagnosis, to elucidate factors that might differentially impact whether girls versus boys meet diagnostic criteria for autism or a related autism spectrum disorder (ASD). Method: Data from a large population-based sample of children were examined. Girls and boys (aged 10-12 years) meeting diagnostic criteria for an ASD were compared with those failing to meet diagnostic criteria despite very high scores on a trait measure of ASD, the Childhood Autism Spectrum Test (CAST). information about behavioral difficulties as reported by teachers, and early estimates of intellectual functioning, were compared. Results: Girls, but not boys, meeting diagnostic criteria for ASD showed significantly more additional problems (low intellectual level, behavioral difficulties) than peers with similarly high CAST scores who did not meet diagnostic criteria. Conclusions: These data suggest that, in the absence of additional intellectual or behavioral problems, girls are less likely than boys to meet diagnostic criteria for ASD at equivalently high levels of autistic-like traits. This might reflect gender bias in diagnosis or genuinely better adaptation/compensation in girls. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(8):788-797.

Mark J. Taylor, Daniel Freeman, Sebastian Lundström, Henrik Larsson, Angelica Ronald (2022)Heritability of Psychotic Experiences in Adolescents and Interaction With Environmental Risk, In: JAMA psychiatry (Chicago, Ill.)79(9)pp. 889-898 American Medical Association

This twin study investigates whether the heritability of psychotic experiences changes with increasing exposure to environmental risks in adolescents.

Angelica Ronald (2015)Recent quantitative genetic research on psychotic experiences: new approaches to old questions, In: Current opinion in behavioral sciences2pp. 81-88 Elsevier

It is common, particularly in young people, to report psychotic experiences (PEs) such as feeling paranoid and having hallucinations. The questions of the role of genes and environment on PEs in the general population, and how PEs relate to schizophrenia, have not, until recently, been addressed empirically. New approaches demonstrate the heritability and role of the environment on the full range of PEs (including positive, cognitive and negative types) and show that extreme, severe forms are linked genetically to milder, less severe forms. New approaches have tested whether PEs are associated with the genome-wide significant genetic variants known to predict schizophrenia. Although at an early stage, this research will impact how we understand PEs in everyday life.

Frank M Spinath, Angelica Ronald, Nicole Harlaar, Thomas S Price, Robert Plomin (2003)Phenotypic g early in life on the etiology of general cognitive ability in a large population sample of twin children aged 2-4 years, In: Intelligence (Norwood)31(2)pp. 195-210 Elsevier
Chloe Austerberry, Maria Mateen, Pasco Fearon, Angelica Ronald (2022)Heritability of Psychological Traits and Developmental Milestones in Infancy A Systematic Review and Meta-analysis, In: JAMA network open5(8)pp. e2227887-e2227887 Amer Medical Assoc

IMPORTANCE Although infancy is the most rapid period of postnatal growth and development, factors associated with variation in infant traits are not well understood. OBJECTIVE To synthesize the large twin study literature partitioning phenotypic variance in psychological traits and developmental milestones in infancy into estimates of heritability and shared and nonshared environment. DATA SOURCES PubMed, PsycINFO, and references of included publications were searched up to February 11, 2021. STUDY SELECTION Peer-reviewed publications using the classical twin design to study psychological traits and developmental milestones from birth to 2 years old were included. DATA EXTRACTION AND SYNTHESIS Data were extracted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and categorized using the International Classification of Functioning, Disability and Health: Children and Youth Version. Data were pooled in 3-level random effects models, incorporating within-cohort variance in outcome measurement and between-cohort variance. Data were analyzed from March 2021 through September 2021. MAIN OUTCOMES AND MEASURES The primary outcomes were monozygotic and dizygotic twin correlations. These were used to calculate genetic and shared and nonshared environment estimates. RESULTS Among 139 publications that were systematically retrieved, data were available on 79 044 twin pairs (31 053 monozygotic and 47 991 dizygotic pairs), 52 independent samples, and 21 countries. Meta-analyses were conducted on psychological traits and developmental milestones from 106 publications organized into 10 categories of functioning, disability, and health. Moderate to high genetic estimates for 8 categories were found, the highest of which was psychomotor functions (pooled h(2), 0.59; 95% CI, 0.25-0.79; P < .001). Several categories of traits had substantial shared environment estimates, the highest being mental functions of language (pooled c(2), 0.59; 95% CI, 0.24-0.86; P = .001). All examined categories of traits had moderate or high nonshared environment estimates, the highest of which were emotional functions (pooled e(2), 0.42; 95% CI, 0.33-0.50; P < .001) and family relationships (pooled e(2), 0.42; 95% CI, 0.30-0.55; P < .001). CONCLUSIONS AND RELEVANCE These findings may be an important source of information to guide future gene discovery research, public perspectives on nature and nurture, and clinical insights into the degree to which family history and environments may estimate major domains of infant functioning, disability, and health in psychological traits and developmental milestones.

Dominika Sieradzka, Robert A Power, Daniel Freeman, Alastair G Cardno, Frank Dudbridge, Angelica Ronald (2015)Heritability of Individual Psychotic Experiences Captured by Common Genetic Variants in a Community Sample of Adolescents, In: Behavior genetics45(5)pp. 493-502

Occurrence of psychotic experiences is common amongst adolescents in the general population. Twin studies suggest that a third to a half of variance in adolescent psychotic experiences is explained by genetic influences. Here we test the extent to which common genetic variants account for some of the twin-based heritability. Psychotic experiences were assessed with the Specific Psychotic Experiences Questionnaire in a community sample of 2152 16-year-olds. Self-reported measures of Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms were obtained. Estimates of SNP heritability were derived and compared to the twin heritability estimates from the same sample. Three approaches to genome-wide restricted maximum likelihood (GREML) analyses were compared: (1) standard GREML performed on full genome-wide data; (2) GREML stratified by minor allele frequency (MAF); and (3) GREML performed on pruned data. The standard GREML revealed a significant SNP heritability of 20 % for Anhedonia (SE = 0.12; p < 0.046) and an estimate of 19 % for Cognitive Disorganization, which was close to significant (SE = 0.13; p < 0.059). Grandiosity and Paranoia showed modest SNP heritability estimates (17 %; SE = 0.13 and 14 %; SE = 0.13, respectively, both n.s.), and zero estimates were found for Hallucinations and Negative Symptoms. The estimates for Anhedonia, Cognitive Disorganization and Grandiosity accounted for approximately half the previously reported twin heritability. SNP heritability estimates from the MAF-stratified approach were mostly consistent with the standard estimates and offered additional information about the distribution of heritability across the MAF range of the SNPs. In contrast, the estimates derived from the pruned data were for the most part not consistent with the other two approaches. It is likely that the difference seen in the pruned estimates was driven by the loss of tagged causal variants, an issue fundamental to this approach. The current results suggest that common genetic variants play a role in the etiology of some adolescent psychotic experiences, however further research on larger samples is desired and the use of MAF-stratified approach recommended.

Emma Colvert, Beata Tick, Fiona McEwen, Catherine Stewart, Sarah R Curran, Emma Woodhouse, Nicola Gillan, Victoria Hallett, Stephanie Lietz, Tracy Garnett, Angelica Ronald, Robert Plomin, Frühling Rijsdijk, Francesca Happé, Patrick Bolton (2015)Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample, In: JAMA psychiatry (Chicago, Ill.)72(5)pp. 415-423

Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population. To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD. We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview-Revised (ADI-R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs). Participants underwent screening using a population-based measure of autistic traits (CAST assessment), structured diagnostic assessments (DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis. On all ASD measures, correlations among monozygotic twins (range, 0.77-0.99) were significantly higher than those for dizygotic twins (range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status (DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors (76%-95%). For the ADI-R only, shared environmental influences were significant (30% [95% CI, 8%-47%]) but smaller than genetic influences (56% [95% CI, 37%-82%]). The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD.

Beate St Pourcain, C. M. A. Haworth, O. S. P. Davis, Kai Wang, Nicholas J. Timpson, David M. Evans, John P. Kemp, Angelica Ronald, Tom Price, Emma Meaburn, Susan M. Ring, Jean Golding, Hakon Hakonarson, R. Plomin, George Davey Smith (2015)Heritability and genome-wide analyses of problematic peer relationships during childhood and adolescence, In: Human genetics134(6)pp. 539-551 Springer Nature

Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population-based birth-cohort (ALSPAC, 4-17 years), and a UK twin sample (TEDS, 4-11 years). Longitudinal twin analysis (TEDS; N currency sign 7,366 twin pairs) showed that peer problems in childhood are heritable (4-11 years, 0.60 < twin-h (2) currency sign 0.71) but genetically heterogeneous from age to age (4-11 years, twin-r (g) = 0.30). GCTA (ALSPAC: N currency sign 5,608, TEDS: N currency sign 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4-12 years, 0.02 < GCTA-h (2)(Meta) currency sign 0.11) though these influences become stronger in adolescence (13-17 years, 0.14 < GCTA-h (2)(ALSPAC) currency sign 0.27). A subsequent cross-sectional genome-wide screen in ALSPAC (N currency sign 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA-P currency sign 0.03). Single variant signals (P currency sign 10(-5)) were followed up in TEDS (N currency sign 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N (Pedigrees) = 793; ACC: N (Cases) = 1,453/N (Controls) = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence.

Kostas A. Papageorgiou, Angelica Ronald (2013)"He who sees things grow from the beginning will have the finest view of them" A systematic review of genetic studies on psychological traits in infancy, In: Neuroscience and biobehavioral reviews37(8)pp. 1500-1517 Elsevier

This paper reviews the studies that have aimed to identify genes influencing psychological traits in infancy (from birth to age 12 months). The review also addresses why genetic research in infancy is worthwhile and what genetic approaches such as genome-wide association studies and next generation sequencing could offer infant genetics. The results revealed that: (a) all studies (N=26) have employed a candidate gene association design; (b) existing studies have most commonly focused on the Dopamine receptor D4 (DRD4) and the Serotonin transporter promoter (5-HTTLPR) gene polymorphisms; (c) phenotypes that have been assessed are temperament, attachment, and attention. Two further studies included both temperament and electrophysiological markers; (d) among many unreplicated findings, the most promising result appeared to be an association between the long DRD4 polymorphism and several "positive" temperament characteristics from birth to 4-months of age and at 12-months of age. It is concluded that, to date, there are limited, and mixed, findings regarding the possible association of genes with psychological phenotypes in infancy. (C) 2013 Elsevier Ltd. All rights reserved.

Oliver Pain, Frank Dudbridge, Alastair G. Cardno, Daniel Freeman, Yi Lu, Sebastian Lundstrom, Paul Lichtenstein, Angelica Ronald, (2018)Genome-wide analysis of adolescent psychotic-like experiences shows genetic overlap with psychiatric disorders, In: American journal of medical genetics. Part B, Neuropsychiatric genetics177(4)pp. 416-425 Wiley

This study aimed to test for overlap in genetic influences between psychotic-like experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic-like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings=6,297-10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic-like experience domain was performed. Single nucleotide polymorphism (SNP)-heritability of each psychotic-like experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium- (LD-) score regression. Genetic overlap between specific psychotic-like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic-like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic-like experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic-like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and major depression.

Grainne Mcloughlin, Angelica Ronald, Jonna Kuntsi, Philip Asherson, Robert Plomin (2007)Genetic support for the dual nature of attention deficit hyperactivity disorder : Substantial genetic overlap between the inattentive and hyperactive-impulsive components, In: Journal of abnormal child psychology35(6)pp. 999-1008 Springer
Elise B. Robinson, Beate St Pourcain, Verneri Anttila, Jack A. Kosmicki, Brendan Bulik-Sullivan, Jakob Grove, Julian Maller, Kaitlin E. Samocha, Stephan J. Sanders, Stephan Ripke, Joanna Martin, Mads V. Hollegaard, Thomas Werge, David M. Hougaard, Benjamin M. Neale, David M. Evans, David Skuse, Preben Bo Mortensen, Anders D. Borglum, Angelica Ronald, George Davey Smith, Mark J. Daly (2016)Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population, In: Nature genetics48(5)pp. 552-555 Springer Nature

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology.

Angelica Ronald, Francesca Happé, Robert Plomin (2006)Genetic Research into Autism, In: Science (American Association for the Advancement of Science)311(5763)pp. 952-952
Wikus Barkhuizen, Oliver Pain, Frank Dudbridge, Angelica Ronald (2020)Genetic overlap between psychotic experiences in the community across age and with psychiatric disorders, In: Translational psychiatry10(1)pp. 86-86

This study explores the degree to which genetic influences on psychotic experiences are stable across adolescence and adulthood, and their overlap with psychiatric disorders. Genome-wide association results were obtained for adolescent psychotic experiences and negative symptom traits (N = 6297-10,098), schizotypy (N = 3967-4057) and positive psychotic experiences in adulthood (N = 116,787-117,794), schizophrenia (N = 150,064), bipolar disorder (N = 41,653), and depression (N = 173,005). Linkage disequilibrium score regression was used to estimate genetic correlations. Implicated genes from functional and gene-based analyses were compared. Mendelian randomization was performed on trait pairs with significant genetic correlations. Results indicated that subclinical auditory and visual hallucinations and delusions of persecution during adulthood were significantly genetically correlated with schizophrenia (r  = 0.27-0.67) and major depression (r  = 0.41-96) after correction for multiple testing. Auditory and visual subclinical hallucinations were highly genetically correlated (r  = 0.95). Cross-age genetic correlations for psychotic experiences were not significant. Gene mapping and association analyses revealed 14 possible genes associated with psychotic experiences that overlapped across age for psychotic experiences or between psychotic experiences and psychiatric disorders. Mendelian randomization indicated bidirectional associations between auditory and visual hallucinations in adults but did not support causal relationships between psychotic experiences and psychiatric disorders. These findings indicate that psychotic experiences in adulthood may be more linked genetically to schizophrenia and major depression than psychotic experiences in adolescence. Our study implicated specific genes that are associated with psychotic experiences across development, as well as genes shared between psychotic experiences and psychiatric disorders.

Wikus Barkhuizen, Frank Dudbridge, Angelica Ronald (2021)Genetic overlap and causal associations between smoking behaviours and mental health, In: Scientific reports11(1)pp. 14871-14871

Cigarette smoking is a modifiable behaviour associated with mental health. We investigated the degree of genetic overlap between smoking behaviours and psychiatric traits and disorders, and whether genetic associations exist beyond genetic influences shared with confounding variables (cannabis and alcohol use, risk-taking and insomnia). Second, we investigated the presence of causal associations between smoking initiation and psychiatric traits and disorders. We found significant genetic correlations between smoking and psychiatric disorders and adult psychotic experiences. When genetic influences on known covariates were controlled for, genetic associations between most smoking behaviours and schizophrenia and depression endured (but not with bipolar disorder or most psychotic experiences). Mendelian randomization results supported a causal role of smoking initiation on psychiatric disorders and adolescent cognitive and negative psychotic experiences, although not consistently across all sensitivity analyses. In conclusion, smoking and psychiatric disorders share genetic influences that cannot be attributed to covariates such as risk-taking, insomnia or other substance use. As such, there may be some common genetic pathways underlying smoking and psychiatric disorders. In addition, smoking may play a causal role in vulnerability for mental illness.

Jonna Kuntsi, Frühling Rijsdijk, Angelica Ronald, Philip Asherson, Robert Plomin (2005)Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood, In: Biological psychiatry (1969)57(6)pp. 647-654 Elsevier Inc

The high heritability of the core symptoms of attention-deficit/hyperactivity disorder (ADHD) has been repeatedly demonstrated, but few studies to date have investigated the extent to which the same genetic influences operate across development or new genes emerge at different developmental periods. We report data from a large, population-based study of approximately 4,000 twin pairs, who have been followed up from early to middle childhood. Parents’ ratings of ADHD symptoms showed moderate stability across the ages, which was mainly due to shared genetic influences. There was also evidence of additional genetic influences, which were not shared with those acting earlier on, emerging at later age periods. The contribution of environmental influences to the stability of the ADHD symptoms over time was small. Parents’ ratings on the Conners’ DSM-IV ADHD subscale at the last assessment point, at an average age of 8 years, did not show the rater contrast effects that were observed in the parents’ ratings at earlier ages with briefer measures. Similar estimates of genetic and environmental influences were obtained for girls and boys. We discuss the implications of the findings for molecular genetic studies on ADHD symptomatology.

Angelica Ronald, Francesca Happé, Patrick Bolton, Lee M Butcher, Thomas S Price, Sally Wheelwright, Simon Baron-Cohen, Robert Plomin (2006)Genetic heterogeneity between the three components of the autism spectrum: a twin study, In: Journal of the American Academy of Child and Adolescent Psychiatry45(6)pp. 691-699

This study investigated the etiology of autistic-like traits in the general population and the etiological overlap between the three aspects of the triad of impairments (social impairments, communication impairments, restricted repetitive behaviors and interests) that together define autism spectrum disorders. Parents of 3,400 8-year-old twin pairs from the Twins Early Development Study completed the Childhood Asperger Syndrome Test, a screening instrument for autism spectrum symptoms in mainstream samples. Genetic model-fitting of categorical and continuous data is reported. High heritability was found for extreme autistic-like traits (0.64-0.92 for various cutoffs) and autistic-like traits as measured on a continuum (0.78-0.81), with no significant shared environmental influences. All three subscales were highly heritable but showed low covariation. In the genetic modeling, distinct genetic influences were identified for the three components. These results suggest the triad of impairments that define autism spectrum disorders is heterogeneous genetically. Molecular genetic research examining the three components separately may identify different causal pathways for the three components. The analyses give no indication that different genetic processes affect extreme autistic impairments and autistic impairments as measured on a continuum, but this can only be directly tested once genes are identified.

Helen Minnis, Joanne Reekie, David Young, Tom O'Connor, Angelica Ronald, Alison Gray, Robert Plomin (2007)Genetic, environmental and gender influences on attachment disorder behaviours, In: British journal of psychiatry190(6)pp. 490-495 Cambridge University Press
Laura Havers, Mark J. Taylor, Angelica Ronald (2019)Genetic and environmental influences on the stability of psychotic experiences and negative symptoms in adolescence, In: Journal of child psychology and psychiatry60(7)pp. 784-792 Wiley

Background Psychotic experiences (PEs) such as paranoia and hallucinations, and negative symptoms (NS) such as anhedonia and flat affect are common in adolescence. Psychotic experiences and negative symptoms (PENS) increase risk for later psychiatric outcomes, particularly when they persist. The extent to which genetic and environmental influences contribute to the stability of PENS in mid-to-late adolescence is unknown. Methods Using the Specific Psychotic Experiences Questionnaire (SPEQ) twice across similar to 9 months in adolescence, N = 1,448 twin pairs [M = 16.32 (0.68)] reported experiences of paranoia, hallucinations, cognitive disorganization, grandiosity and anhedonia, and their parents reported on a range of NS. Individuals were split into low-scoring, decreasing, increasing and persistent groups for each subscale. Frequencies and mean differences in distress, depression traits and emotional problems were investigated across groups. Longitudinal structural equation modelling was used to estimate the aetiological components underlying the stability of PENS. Results Phenotypic stability was moderate for all PENS (r = .59-.69). Persistent PENS across 9 months were associated with greater levels of distress (V = 0.15-0.46, for PEs only), depression traits (d = 0.47-1.67, except grandiosity) and emotional problems (d = 0.47-1.47, except grandiosity and anhedonia) at baseline compared to groups with transitory or low levels of PENS. At both ages PENS were heritable and influenced by shared and nonshared environment. Genetic influences contributed 38%-62% and shared environment contributed 13%-33% to the stability of PENS. Nonshared environment contributed 34%-41% (12% for parent-rated NS). There was strong overlap of genetic and shared environmental influences across time, and lower overlap for nonshared environment. Imperfect stability of PENS was at least partly due to nonshared environmental influences. Conclusions When adolescent PENS persist over time, they are often characterized by more distress, and higher levels of other psychopathology. Both genetic and environmental effects influence stability of PENS.

Angelica Ronald, Lisa R. Edelson, Philip Asherson, Kimberly J. Saudino (2010)Exploring the Relationship Between Autistic-Like Traits and ADHD Behaviors in Early Childhood: Findings from a Community Twin Study of 2-Year-Olds, In: Journal of abnormal child psychology38(2)pp. 185-196 Springer US

Behaviors characteristic of autism and ADHD emerge in early childhood, yet research investigating their comorbidity has focused on older children. This study aimed to explore the nature of the relationship between autistic-like traits and ADHD behaviors in a community sample of 2-year-olds. Twins from the Boston University Twin Project ( N  = 312 pairs) were assessed by their parents on autistic-like traits and ADHD behaviors using the Childhood Behavior Checklist. Phenotypic analyses showed that after controlling for general cognitive ability and socioeconomic status, autistic-like traits (total scale as well as social and nonsocial subscales) correlated positively with ADHD behaviors ( r  = 0.23–0.26). Structural equation model-fitting analyses revealed that there were modest shared genetic influences between ADHD- and autistic traits (genetic correlation = 0.27) as well as some common environmental influences explaining their covariation. Implications for identifying shared biological pathways underlying autistic-like traits and ADHD behaviors are discussed.

Angelica Ronald, Francesca Happé, Katharina Dworzynski, Patrick Bolton, Robert Plomin (2010)Exploring the Relation Between Prenatal and Neonatal Complications and Later Autistic-Like Features in a Representative Community Sample of Twins, In: Child development81(1)pp. 166-182 Blackwell Publishing Ltd
Victoria Hallett, Angelica Ronald, Emma Colvert, Catherine Ames, Emma Woodhouse, Stephanie Lietz, Tracy Garnett, Nicola Gillan, Fruhling Rijsdijk, Lawrence Scahill, Patrick Bolton, Francesca Happe (2013)Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls, In: Journal of child psychology and psychiatry54(11)pp. 1176-1185 Wiley

BackgroundAlthough many children with autism spectrum disorders (ASDs) experience difficulties with anxiety, the manifestation of these difficulties remains unresolved. The current study assessed anxiety in a large population-based twin sample, aged 10-15years. Phenotypic analyses were used to explore anxiety symptoms in children with ASDs, their unaffected co-twins and a control sample. MethodsParticipants included 146 families from the Twins Early Development Study (TEDS) where one or both children had a suspected ASD. Eighty control families were also included. The Revised Child Anxiety and Depression scale (Chorpita, Yim, Moffitt, Umemoto & Francis, 2000) was completed (self- and parent-report), along with diagnostic and cognitive tests. Children were categorized into four groups (a) ASD (b) Broader Autism Phenotype (BAP: mainly co-twins of children with ASDs, with high subclinical autistic traits) (c) unaffected co-twins (with neither ASDs nor BAP) (d) controls. ResultsChildren in the ASD and BAP groups scored significantly higher than controls for all parent-rated (although not child-rated) anxiety subscales. There were no significant differences between the ASD and BAP groups for any of the parent-rated anxiety subscales. Compared with controls, unaffected co-twins showed significantly heightened Social Anxiety, Generalized Anxiety, and Panic symptoms. Significant associations were observed between certain anxiety subscales and both IQ and ASD symptoms. For example, greater parent-rated Social Anxiety was associated with higher IQ and increased social and communicative impairments. Significant interrater correlations were observed for anxiety reports in children with ASDs (r=.27-.54; p

Agnieszka Gidziela, Margherita Malanchini, Kaili Rimfeld, Andrew McMillan, Angelica Ronald, Essi Viding, Alison Pike, Kathryn Asbury, Thalia C. Eley, Sophie von Stumm, Robert Plomin (2022)Explaining the influence of non-shared environment (NSE) on symptoms of behaviour problems from preschool to adulthood: mind the missing NSE gap, In: Journal of child psychology and psychiatry Wiley

BackgroundIndividual differences in symptoms of behaviour problems in childhood and adolescence are not primarily due to nature or nurture - another substantial source of variance is non-shared environment (NSE). However, few specific environmental factors have been found to account for these NSE estimates. This creates a 'missing NSE' gap analogous to the 'missing heritability' gap, which refers to the shortfall in identifying DNA differences responsible for heritability. We assessed the extent to which variance in behaviour problem symptoms during the first two decades of life can be accounted for by measured NSE effects after controlling for genetics and shared environment. MethodsThe sample included 4,039 pairs of twins in the Twins Early Development Study whose environments and symptoms of behaviour problems were assessed in preschool, childhood, adolescence and early adulthood via parent, teacher and self-reports. Twin-specific environments were assessed via parent-reports, including early life adversity, parental feelings, parental discipline and classroom environment. Multivariate longitudinal twin model-fitting was employed to estimate the variance in behaviour problem symptoms at each age that could be predicted by environmental measures at the previous age. ResultsOn average across childhood, adolescence and adulthood, parent-rated NSE composite measures accounted for 3.4% of the reliable NSE variance (1.0% of the total variance) in parent-rated, symptoms of behaviour problems, 0.5% (0.1%) in teacher-rated symptoms and 0.9% (0.5%) in self-rated symptoms after controlling for genetics, shared environment and error of measurement. Cumulatively across development, our parent-rated NSE measures in preschool, childhood and adolescence predicted 4.7% of the NSE variance (2.0% of the total variance) in parent-rated and 0.3% (0.2%) in self-rated behaviour problem symptoms in adulthood. ConclusionsThe missing NSE gap between variance explained by measured environments and total NSE variance is large. Home and classroom environments are more likely to influence behaviour problem symptoms via genetics than via NSE.

Elizabeth O'Nions, Beata Tick, Fruhling Rijsdijk, Francesca Happe, Robert Plomin, Angelica Ronald, Essi Viding (2015)Examining the Genetic and Environmental Associations between Autistic Social and Communication Deficits and Psychopathic Callous-Unemotional Traits, In: PloS one10(9)pp. e0134331-e0134331 Public Library Science

Background Difficulties in appropriate social interaction are characteristic of both children with autism spectrum disorders and children with callous-unemotional traits (who are at risk of developing psychopathy). Extant experimental studies suggest that the nature of atypical social cognition that characterises these two profiles is not identical. However, 'empathizing' difficulties have been hypothesised for both groups, raising questions about the degree of aetiological separation between social impairments that characterize each disorder. This study explored the relative contribution of independent vs. shared aetiological influences to social and communication impairments associated with autistic traits and callous-unemotional traits, indexed by parent-report in a population-based cohort of twins. Methods Participants were over 5,000 twin pairs from a UK cohort (the Twins Early Development Study; TEDS), assessed for callous-unemotional traits at 7 years and autistic social and communication impairments at 8 years. Multivariate model-fitting was used to explore the relative contribution of independent vs. overlapping genetic/environmental influences on these traits. Results Both social and communication impairments and callous-unemotional traits were highly heritable, although the genetic and environmental influences accounting for individual differences on each domain were predominantly independent. Conclusions Extant evidence from experimental and neuro-imaging studies has suggested that, despite some superficially overlapping behaviours, the social difficulties seen in children with autism spectrum disorders and callous-unemotional traits are largely distinct. The current study is the first to demonstrate considerable aetiological independence of the social interaction difficulties seen in children with autism spectrum disorders and those with callous-unemotional traits.

M. J. Taylor, A. Ronald, J. Martin, Sebastian Lundström, G. M. Hosang, P. Lichtenstein, (2022)Examining the association between childhood autistic traits and adolescent hypomania: A longitudinal twin study, In: Psychological medicine52(15)pp. 3606-3615

Background There is evidence that autism spectrum disorders (ASDs) co-occur with bipolar disorder (BD) relatively frequently. Individuals with BD often report symptoms of mania and hypomania during adolescence, prior to the age of onset for BD. It is unknown whether these symptoms are associated with ASDs. We examined whether diagnoses of ASDs and autistic traits were associated with hypomania in a large, population-based Swedish twin sample. Methods Parental structured interviews assessed autistic traits, and were used to assign screening diagnoses of ASDs, when twins were aged 9 or 12 (N = 13 533 pairs). Parents then completed questionnaires assessing hypomania when the twins were aged 15 and 18 (N = 3852 pairs at age 15, and 3013 pairs at age 18). After investigating the phenotypic associations between these measures, we used the classical twin design to test whether genetic and environmental influences on autistic traits influence variation in adolescent hypomania. Results Autistic traits and ASD diagnoses in childhood were associated with elevated scores on the measures of adolescent hypomania. Twin analyses indicated that 6-9% of the variance in hypomania was explained by genetic influences that were shared with autistic traits in childhood. When repeating these analyses for specific autistic trait domains, we found a stronger association between social interaction difficulties and hypomania than for other autistic trait domains. Conclusions These results indicate a genetic link between autistic traits and hypomania in adolescence. This adds to the growing evidence base of genetic factors associated with ASDs showing links with psychiatric outcomes across childhood and into adulthood. Copyright © The Author(s), 2021. Published by Cambridge University Press.

Elise B. Robinson, Paul Lichtenstein, Henrik Anckarsäter, Francesca Happé, Angelica Ronald, (2013)Examining and interpreting the female protective effect against autistic behavior, In: Proceedings of the National Academy of Sciences - PNAS110(13)pp. 5258-5262 National Academy of Sciences

Male preponderance in autistic behavioral impairment has been explained in terms of a hypothetical protective effect of female sex, yet little research has tested this hypothesis empirically. If females are protected, they should require greater etiologic load to manifest the same degree of impairment as males. The objective of this analysis was to examine whether greater familial etiologic load was associated with quantitative autistic impairments in females compared with males. Subjects included 3,842 dizygotic twin pairs from the Twins Early Development Study (TEDS) and 6,040 dizygotic twin pairs from the Child and Adolescent Twin Study of Sweden (CATSS). In both samples, we compared sibling autistic traits between female and male probands, who were identified as children scoring in the top 90th and 95th percentiles of the population autistic trait distributions. In both TEDS and CATSS, siblings of female probands above the 90th percentile had significantly more autistic impairments than the siblings of male probands above the 90th percentile. The siblings of female probands above the 90th percentile also had greater categorical recurrence risk in both TEDS and CATSS. Results were similar in probands above the 95th percentile. This finding, replicated across two nationally-representative samples, suggests that female sex protects girls from autistic impairments and that girls may require greater familial etiologic load to manifest the phenotype. It provides empirical support for the hypothesis of a female protective effect against autistic behavior and can be used to inform and interpret future gene finding efforts in autism spectrum disorders.

Elise B. Robinson, Karestan C. Koenen, Marie C. McCormick, Kerim Munir, Victoria Hallett, Francesca Happe, Robert Plomin, Angelica Ronald (2011)Evidence That Autistic Traits Show the Same Etiology in the General Population and at the Quantitative Extremes (5%, 2.5%, and 1%), In: Archives of general psychiatry68(11)pp. 1113-1121 Amer Medical Assoc

Context: Genetic factors play an important role in the etiology of both autism spectrum disorders and autistic traits. However, little is known about the etiologic consistency of autistic traits across levels of severity. Objective: To compare the etiology of typical variation in autistic traits with extreme scoring groups (including top 1%) that mimicked the prevalence of diagnosed autism spectrum disorders in the largest twin study of autistic traits to date. Design: Twin study using phenotypic analysis and genetic model-fitting in the total sample and extreme scoring groups (top 5%, 2.5%, and 1%). Setting: A nationally representative twin sample from the general population of England. Participants: The families of 5968 pairs aged 12 years old in the Twins' Early Development Study. Main Outcome Measure: Autistic traits as assessed by the Childhood Autism Spectrum Test. Results: Moderate to high heritability was found for autistic traits in the general population (53% for females and 72% for males). High heritability was found in extreme-scoring groups. There were no differences in heritability among extreme groups or between the extreme groups and the general population. A continuous liability shift toward autistic trait affectedness was seen in the cotwins of individuals scoring in the top 1%, suggesting shared etiology between extreme scores and normal variation. Conclusion: This evidence of similar etiology across normal variation and the extremes has implications for molecular genetic models of autism spectrum disorders and for conceptualizing autism spectrum disorders as the quantitative extreme of a neurodevelopmental continuum.

Angelica Ronald, Emily Simonoff, Jonna Kuntsi, Philip Asherson, Robert Plomin (2008)Evidence for overlapping genetic influences on autistic and ADHD behaviours in a community twin sample, In: Journal of child psychology and psychiatry49(5)pp. 535-542 Wiley

Background: High levels of clinical comorbidity have been reported between autistic spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). This study takes an individual differences approach to determine the degree of phenotypic and aetiological overlap between autistic traits and ADHD behaviours in the general population. Methods: The Twins Early Development Study is a community sample born in England and Wales. Families with twins born in 1994-6 were invited to join; 6,771 families participated in the study when the twins were 8 years old. Parents completed the Childhood Asperger Syndrome Test and the Conners' DSM-IV subscales. Teacher data were also collected on a sub-sample. High scores on the Conners' subscales were used to identify possible ADHD cases. Potential ASD cases were interviewed using the Development and Well-Being Assessment. Multivariate structural equation model-fitting was employed, as well as DeFries Fulker extremes analysis and liability threshold model-fitting. Results: Significant correlations were found between autistic and ADHD traits in the general population (.54 for parent data, .51 for teacher data). In the bivariate models, all genetic correlations were >.50, indicating a moderate degree of overlap in genetic influences on autistic and ADHD traits, both throughout the general population and at the quantitative extreme. This phenotypic and genetic overlap still held when sex, IQ and conduct problems were controlled for, for both parent and teacher data. There was also substantial overlap in suspected cases (41% of children who met criteria for an ASD had suspected ADHD; 22% with suspected ADHD met criteria for an ASD). Conclusions: These results suggest there are some common genetic influences operating across autistic traits and ADHD behaviours throughout normal variation and at the extreme. This is relevant for molecular genetic research, as well as for psychiatrists and psychologists, who may have assumed these two sets of behaviours are independent.

Angelica Ronald (2022)Editorial: Transdiagnostic research: transitory or transformative?, In: Journal of child psychology and psychiatry63(7)pp. 721-723
Angelica Ronald (2019)Editorial: The psychopathology p factor: will it revolutionise the science and practice of child and adolescent psychiatry?, In: Journal of child psychology and psychiatry60(5)pp. 497-499 Wiley

The psychopathology p factor has emerged from a series of strong empirical studies, largely in the adult psychiatry literature. Here, some of the recent findings relating to the p factor in children and adolescents are considered and the implications for child and adolescent psychiatry are discussed. Is it essential to covary for 'p' when we study specific domains of psychopathology? Do neurodevelopmental conditions make up part of the psychopathology p factor? How do we treat the 'p factor' in clinics? This editorial considers some of the contributions from this issue of Journal of Child Psychology and Psychiatry together with the wider literature that speak to these issues.

Barbara Franke, Eric Fombonne, Angelica Ronald (2021)Editorial: The new genetics of autism, In: Journal of child psychology and psychiatry62(11)pp. 1271-1273 Wiley
Angelica Ronald (2020)Editorial: Polygenic scores in child and adolescent psychiatry - strengths, weaknesses, opportunities and threats, In: Journal of child psychology and psychiatry61(5)pp. 519-521 Wiley

Polygenic scores estimate an individual's genetic liability for a particular disorder or trait. They are based on current knowledge of the trait's genetic architecture and focus on common genetic variants. In this editorial, I will discuss some of the strengths, weaknesses, opportunities and threats (SWOT) to polygenic scores within the context of child and adolescent psychiatry. I consider how the potential application of polygenic scores in health settings has some parallels with existing practices, but that polygenic scores also undoubtedly raise unique challenges. This SWOT analysis is accompanied by discussion of some new findings using polygenic scores in this issue of Journal of Child Psychology and Psychiatry.

Chloe Austerberry, Pasco Fearon, Angelica Ronald, Leslie D Leve, Jody M Ganiban, Misaki N Natsuaki, Daniel S Shaw, Jenae M Neiderhiser, David Reiss (2022)Early manifestations of intellectual performance: Evidence that genetic effects on later academic test performance are mediated through verbal performance in early childhood, In: Child development93(2)pp. e188-e206

Intellectual performance is highly heritable and robustly predicts lifelong health and success but the earliest manifestations of genetic effects on this asset are not well understood. This study examined whether early executive function (EF) or verbal performance mediate genetic influences on subsequent intellectual performance, in 561 U.S.-based adoptees (57% male) and their birth and adoptive parents (70% and 92% White, 13% and 4% African American, 7% and 2% Latinx, respectively), administered measures in 2003-2017. Genetic influences on children's academic performance at 7 years were mediated by verbal performance at 4.5 years (β = .22, 95% CI [0.08, 0.35], p = .002) and not via EF, indicating that verbal performance is an early manifestation of genetic propensity for intellectual performance.

Mark J. Taylor, Alice M. Gregory, Daniel Freeman, Angelica Ronald (2015)Do Sleep Disturbances and Psychotic-Like Experiences in Adolescence Share Genetic and Environmental Influences?, In: Journal of abnormal psychology (1965)124(3)pp. 674-684 Amer Psychological Assoc

Sleep disturbances regularly co-occur with clinical psychotic disorders and dimensions of psychotic-like experiences (PLEs). One possible explanation for this, which has yet to be tested, is that similar genetic or environmental influences underlie sleep disturbances and vulnerability to PLEs. We conducted a twin study to test this possibility in relation to sleep disturbances and six specific PLEs in adolescence in the general population. Approximately 5,000 16-year-old twin pairs completed the Pittsburgh Sleep Quality Index and Insomnia Severity Index. PLEs were assessed using the Specific PLEs Questionnaire, comprising five self-report subscales (Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, and Anhedonia) and one parent-report subscale (Negative Symptoms). The associations between these measures were tested using structural equation twin model fitting. Paranoia, Hallucinations, and Cognitive Disorganization displayed moderate and significant correlations with both sleep measures (0.32-.42), while Negative Symptoms, Anhedonia, and Grandiosity showed lower correlations (0.01-0.17). Genetic and environmental influences significantly overlapped across PLEs (Paranoia, Hallucinations, Cognitive Disorganization) and both types of sleep disturbance (mean genetic and nonshared environmental correlations = 0.54 and 0.24, respectively). These estimates reduced, yet remained significant, after controlling for negative affect. The association between PLEs with sleep disturbances in adolescence is partly due to genetic and environmental influences that are common to them both. These findings indicate that the known neurobiology of sleep disturbance may provide clues regarding the causes of PLEs in adolescence.

Victoria Hallett, Angelica Ronald, Fruhling Rijsdijk, Francesca Happe (2012)Disentangling the Associations Between Autistic-Like and Internalizing Traits: A Community Based Twin Study, In: Journal of abnormal child psychology40(5)pp. 815-827 Springer Nature

Internalizing difficulties are prevalent in children with autism spectrum disorders (ASD), yet little is known about the underlying cause of this comorbidity. It is also unclear which types of autistic-like and internalizing difficulties are most strongly associated. The current study investigated the phenotypic and etiological associations between specific autistic-like traits and internalizing traits within a population-based sample. Parent-reported data were analyzed from 7,311 twin pairs at age 7 to 8 years. Structural equation modeling revealed distinguishable patterns of overlap between the three autistic-like traits (social difficulties, communication problems and repetitive/restricted behaviors) and four subtypes of internalizing traits (social anxiety, fears, generalized anxiety, negative affect). Although all phenotypic associations were modest (rph = 0.00-0.36), autistic-like communication impairments and repetitive/restricted behaviors correlated most strongly with generalized anxiety and negative affect both phenotypically and genetically. Conversely, autistic-like social difficulties showed little overlap with internalizing behaviors. Disentangling these associations and their etiological underpinnings may help contribute to the conceptualization and diagnosis of 'comorbidity' within ASD and internalizing disorders.

Mark J. Taylor, Daniel Freeman, Angelica Ronald (2016)Dimensional psychotic experiences in adolescence: Evidence from a taxometric study of a community-based sample, In: Psychiatry research241pp. 35-42 Elsevier

Psychotic experiences of varying severity levels are common in adolescence. It is not known whether beyond a certain severity in the general population, psychotic experiences represent a categorically distinct phenomena to milder psychotic experiences. We employed taxometric analytic procedures to determine whether psychotic experiences in adolescence are taxonic (i.e. categorical) or dimensional. Six different psychotic experiences were assessed in a community sample of approximately 5000 adolescents. Three taxometric procedures were conducted. Across all procedures, there was no evidence of a taxon (i.e. a separate latent population) underlying psychotic experiences in adolescence. Rather, a dimensional structure was supported. The results support the notion that psychotic experiences are continuously distributed throughout the general population, and there is no clear discontinuity between milder and more severe psychotic experiences. Thus, these findings support the use of dimensional approaches to understanding psychotic experiences in etiological studies. In clinical practice, categorical cut-offs are needed: the present findings show that a 'natural' break point is not present for identifying severe psychotic experiences, and it is likely therefore that other criteria (such as general functioning) might better aid decision-making with regards to identifying individuals with severe psychotic experiences in need of care during adolescence. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license.

Fiona S McEwen, Catherine S Stewart, Emma Colvert, Emma Woodhouse, Sarah Curran, Nicola Gillan, Victoria Hallett, Stephanie Lietz, Tracy Garnett, Angelica Ronald, Declan Murphy, Francesca Happé, Patrick Bolton (2016)Diagnosing autism spectrum disorder in community settings using the Development and Well-Being Assessment: validation in a UK population-based twin sample, In: Journal of child psychology and psychiatry57(2)pp. 161-170

Increasing numbers of people are being referred for the assessment of autism spectrum disorder (ASD). The NICE (UK) and the American Academy of Pediatrics recommend gathering a developmental history using a tool that operationalises ICD/DSM criteria. However, the best-established diagnostic interview instruments are time consuming, costly and rarely used outside national specialist centres. What is needed is a brief, cost-effective measure validated in community settings. We tested the Development and Well-Being Assessment (DAWBA) for diagnosing ASD in a sample of children/adolescents representative of those presenting in community mental health settings. A general population sample of twins (TEDS) was screened and 276 adolescents were selected as at low (CAST score < 12; n = 164) or high risk for ASD (CAST score ≥ 15 and/or parent reported that ASD suspected/previously diagnosed; n = 112). Parents completed the ASD module of the DAWBA interview by telephone or online. Families were visited at home: the ADI-R and autism diagnostic observation schedule (ADOS) were completed to allow a best-estimate research diagnosis of ASD to be made. Development and Well-Being Assessment ASD symptom scores correlated highly with ADI-R algorithm scores (ρ = .82, p < .001). Good sensitivity (0.88) and specificity (0.85) were achieved using DAWBA computerised algorithms. Clinician review of responses to DAWBA questions minimally changed sensitivity (0.86) and specificity (0.87). Positive (0.82-0.95) and negative (0.90) predictive values were high. Eighty-six per cent of children were correctly classified. Performance was improved by using it in conjunction with the ADOS. The DAWBA is a brief structured interview that showed good sensitivity and specificity in this general population sample. It requires little training, is easy to administer (online or by interview) and diagnosis is aided by an algorithm. It holds promise as a tool for assisting with assessment in community settings and may help services implement the recommendations made by NICE and the American Academy of Pediatrics regarding diagnosis of young people on the autism spectrum.

Katharina Dworzynski, Angelica Ronald, Marianna E. Hayiou-Thomas, Fiona McEwan, Francesca Happe, Patrick Bolton, Robert Plomin (2008)Developmental path between language and autistic-like impairments: A twin study, In: Infant and child development17(2)pp. 121-136 Wiley

Autism spectrum disorders (ASDs) are diagnosed when individuals show impairments in three behavioural domains: communication, social interactions, and repetitive, restrictive behaviours and interests (RRBIs). Recent data suggest that these three sets of behaviours are genetically heterogeneous. Early language delay is strongly associated with ASD, but the basis for this association and the relationship with individual sub-domains of ASD has not been systematically investigated. In the present study, data came from a population-based twin sample with language development data at 2-4 years, measured by the MacArthur Communicative Development Inventory (MCDI), and data at 8 years using the Childhood Asperger Syndrome Test (CAST). For the total CAST and the three subscales at 8 years, approximately 300 same-sex twin pairs were selected as showing extreme autistic-like traits (ALTs), defined here as pairs in which at least one member of the twin pair scored in the highest 5% of the distribution. Phenotypic analyses indicated that children showing extreme social and communication ALTs (but not the RRBI subscale) at 8 years were below average in language development at 2-4 years. A regression model for selected twin data suggested that genetic influences account for this overlap, but that these effects are only in part mediated by genes that are shared between language and extreme autistic traits. Copyright (C) 2008 John Wiley & Sons, Ltd.

Laurie J. Hannigan, Ragna Bugge Askeland, Helga Ask, Martin Tesli, Elizabeth Corfield, Ziada Ayorech, Per Magnus, Pal Rasmus Njolstad, Anne-Siri Oyen, Camilla Stoltenberg, Ole A. Andreassen, Angelica Ronald, George Davey Smith, Ted Reichborn-Kjennerud, Alexandra Havdahl (2021)Developmental milestones in early childhood and genetic liability to neurodevelopmental disorders, In: Psychological medicinepp. 1-9 Cambridge Univ Press

Background Timing of developmental milestones, such as age at first walking, is associated with later diagnoses of neurodevelopmental disorders. However, its relationship to genetic risk for neurodevelopmental disorders in the general population is unknown. Here, we investigate associations between attainment of early-life language and motor development milestones and genetic liability to autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Methods We use data from a genotyped sub-set (N = 25699) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). We calculate polygenic scores (PGS) for autism, ADHD, and schizophrenia and predict maternal reports of children's age at first walking, first words, and first sentences, motor delays (18 months), and language delays and a generalised measure of concerns about development (3 years). We use linear and probit regression models in a multi-group framework to test for sex differences. Results We found that ADHD PGS were associated with earlier walking age (beta = -0.033, p(adj) < 0.001) in both males and females. Additionally, autism PGS were associated with later walking (beta = 0.039, p(adj) = 0.006) in females only. No robust associations were observed for schizophrenia PGS or between any neurodevelopmental PGS and measures of language developmental milestone attainment. Conclusions Genetic liabilities for neurodevelopmental disorders show some specific associations with the age at which children first walk unsupported. Associations are small but robust and, in the case of autism PGS, differentiated by sex. These findings suggest that early-life motor developmental milestone attainment is associated with genetic liability to ADHD and autism in the general population.

M. J. Taylor, T. Charman, E. B. Robinson, R. Plomin, F. Happe, P. Asherson, A. Ronald (2013)Developmental associations between traits of autism spectrum disorder and attention deficit hyperactivity disorder: a genetically informative, longitudinal twin study, In: Psychological medicine43(8)pp. 1735-1746 Cambridge Univ Press

Background. Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and associated subclinical traits, regularly co-occur with one another. However, the aetiology of their co-occurrence remains poorly understood. This paper provides the first genetically informative, longitudinal analysis of the interaction between traits of ASD and ADHD, and explores their genetic and environmental overlap. Method. Parents of approximately 5000 twin pairs completed questionnaires assessing traits of ASD and ADHD when twins were aged 8 and 12 years. Cross-lagged longitudinal modelling explored their developmental association, enabling a consideration of phenotypic-driven processes. Overlapping aetiological influences on traits at age 12 years were explored using bivariate twin modelling. Results. Traits of ADHD at age 8 years were more strongly predictive of traits of ASD at 12 years than traits of ASD at 8 years were of traits of ADHD at 12 years. Analysis of traits by subscales assessing specific symptom domains suggested that communication difficulties were most strongly associated with traits of ADHD. Bivariate modelling suggested moderate genetic overlap on traits in males (genetic correlation=0.41), and a modest degree of overlap in females (genetic correlation=0.23) at age 12 years. Conclusions. Traits of ADHD at age 8 years significantly influence traits of ASD at age 12 years, after controlling for their initial relationship at age 8 years. In particular, early ADHD traits influenced later communication difficulties. These findings demonstrate the dynamic nature of co-occurring traits across development. In addition, these findings add to a growing body of literature suggesting that traits of ASD and ADHD may arise via similar aetiological processes.

Helena M. S. Zavos, Daniel Freeman, Claire M. A. Haworth, Philip McGuire, Robert Plomin, Alastair G. Cardno, Angelica Ronald (2014)Consistent Etiology of Severe, Frequent Psychotic Experiences and Milder, Less Frequent Manifestations A Twin Study of Specific Psychotic Experiences in Adolescence, In: JAMA psychiatry (Chicago, Ill.)71(9)pp. 1049-1057 Amer Medical Assoc

a IMPORTANCE The onset of psychosis is usually preceded by psychotic experiences (PE). Little is known about the etiology of PE and whether the degree of genetic and environmental influences varies across different levels of severity. A recognized challenge is to identify individuals at high risk of developing psychotic disorders prior to disease onset. OBJECTIVES To investigate the degree of genetic and environmental influences on specific PE, assessed dimensionally, in adolescents in the community and in those who have many, frequent experiences (defined using quantitative cutoffs). We also assessed the degree of overlap in etiological influences between specific PE. DESIGN, SETTING, AND PARTICIPANTS Structural equation model-fitting, including univariate and bivariate twin models, liability threshold models, DeFries-Fulker extremes analysis, and the Cherny method, was used to analyze a representative community sample of 5059 adolescent twin pairs (mean [SD] age, 16.31 [0.68] years) from England and Wales. MAIN OUTCOMES AND MEASURES Psychotic experiences assessed as quantitative traits (self-rated paranoia, hallucinations, cognitive disorganization, grandiosity, and anhedonia, as well as parent-rated negative symptoms). RESULTS Genetic influences were apparent for all PE (15%-59%), with modest shared environment for hallucinations and negative symptoms (17%-24%) and significant nonshared environment (49%-64%) for the self-rated scales and 17% for parent-rated negative symptoms. Three empirical approaches converged to suggest that the etiology in extreme-scoring groups (most extreme scoring: 5%, 10%, and 15%) did not differ significantly from that of the whole distribution. There was no linear change in heritability across the distribution of PE, with the exception of a modest increase in heritability for increasing severity of parent-rated negative symptoms. Of the PE that showed covariation, this appeared to be due to shared genetic influences (bivariate heritabilities, 0.54-0.71). CONCLUSIONS AND RELEVANCE These findings are consistent with the concept of a psychosis continuum, suggesting that the same genetic and environmental factors influence both extreme, frequent PE and milder, less frequent manifestations in adolescents. Individual PE in adolescence, assessed quantitatively, have lower heritability estimates and higher estimates of nonshared environment than those for the liability to schizophrenia. Heritability varies by type of PE, being highest for paranoia and parent-rated negative symptoms and lowest for hallucinations.

Timothy Singham, Essi Viding, Tabea Schoeler, Louise Arseneault, Angelica Ronald, Charlotte M. Cecil, Eamon McCrory, Frulhing Rijsdijk, Jean-Baptiste Pingault (2017)Concurrent and Longitudinal Contribution of Exposure to Bullying in Childhood to Mental Health The Role of Vulnerability and Resilience, In: JAMA psychiatry (Chicago, Ill.)74(11)pp. 1112-1119 Amer Medical Assoc

IMPORTANCE: Exposure to bullying is associated with poor mental health. However, the degree to which observed associations reflect direct detrimental contributions of exposure to bullying to mental health remains uncertain, as noncausal relationships may arise from genetic and environmental confounding (eg, preexisting vulnerabilities). Determining to what extent exposure to bullying contributes to mental health is an important concern, with implications for primary and secondary interventions. OBJECTIVE: To characterize the concurrent and longitudinal contribution of exposure to bullying to mental health in childhood and adolescence using a twin differences design to strengthen causal inference. DESIGN, SETTING, AND PARTICIPANTS: Participants were drawn from the Twins Early Development Study, a population-based cohort recruited from population records of births in England and Wales between January 1, 1994, and December 31, 1996. Data collection took place when the participants were between 11 and 16 years of age from December 1, 2005, to January 31, 2013. Data analysis was conducted from January 1, 2016, to June 20, 2017. EXPOSURES: Participants completed the Multidimensional Peer-Victimization Scale at 11 and 14 years of age. MAIN OUTCOMES AND MEASURES: Mental health assessments at 11 and 16 years of age included anxiety, depression, hyperactivity and impulsivity, inattention, conduct problems, and psychotic-like experiences (eg, paranoid thoughts or cognitive disorganization). RESULTS: The 11108 twins included in the final sample (5894 girls and 5214 boys) were a mean age of 11.3 years at the first assessment and 16.3 years at the last assessment. The most stringent twin differences estimates (monozygotic) were consistent with causal contribution of exposure to bullying at 11 years to concurrent anxiety, depression, hyperactivity and impulsivity, inattention, and conduct problems. Effects decreased over time; that is, substantial concurrent contributions to anxiety (beta = 0.27; 95% CI, 0.22-0.33) persisted for 2 years (beta = 0.12; 95% CI, 0.04-0.20) but not 5 years. Direct contributions to paranoid thoughts and cognitive disorganization persisted for 5 years. CONCLUSIONS AND RELEVANCE: This study is the largest to date to characterize the contribution of exposure to bullying in childhood to mental health using a twin differences design and multi-informant, multiscale data. Stringent evidence of the direct detrimental contribution of exposure to bullying in childhood to mental health is provided. Findings also suggest that childhood exposure to bullying may partly be viewed as a symptom of preexisting vulnerabilities. Finally, the dissipation of effects over time for many outcomes highlights the potential for resilience in children who were bullied. In addition to programs that aim to reduce exposure to bullying, interventions may benefit from addressing preexisting vulnerabilities and focus on resilience.

Rosa Cheesman, Saskia Selzam, Angelica Ronald, Philip S. Dale, Tom A. McAdams, Thalia C. Eley, Robert Plomin (2017)Childhood behaviour problems show the greatest gap between DNA-based and twin heritability, In: Translational psychiatry7(12)pp. 1-9 Springer Nature

For most complex traits, DNA-based heritability ('SNP heritability') is roughly half that of twin-based heritability. A previous report from the Twins Early Development Study suggested that this heritability gap is much greater for childhood behaviour problems than for other domains. If true, this finding is important because SNP heritability, not twin heritability, is the ceiling for genome-wide association studies. With twice the sample size as the previous report, we estimated SNP heritabilities (N up to 4653 unrelated individuals) and compared them with twin heritabilities from the same sample (N up to 4724 twin pairs) for diverse domains of childhood behaviour problems as rated by parents, teachers, and children themselves at ages 12 and 16. For 37 behaviour problem measures, the average twin heritability was 0.52, whereas the average SNP heritability was just 0.06. In contrast, results for cognitive and anthropometric traits were more typical (average twin and SNP heritabilities were 0.58 and 0.28, respectively). Future research should continue to investigate the reasons why SNP heritabilities for childhood behaviour problems are so low compared with twin estimates, and find ways to maximise SNP heritability for genome-wide association studies.

Angelica Ronald, Dominika Sieradzka, Alastair G Cardno, Claire M A Haworth, Philip McGuire, Daniel Freeman (2014)Characterization of psychotic experiences in adolescence using the specific psychotic experiences questionnaire: findings from a study of 5000 16-year-old twins, In: Schizophrenia bulletin40(4)pp. 868-877

We aimed to characterize multiple psychotic experiences, each assessed on a spectrum of severity (ie, quantitatively), in a general population sample of adolescents. Over five thousand 16-year-old twins and their parents completed the newly devised Specific Psychotic Experiences Questionnaire (SPEQ); a subsample repeated it approximately 9 months later. SPEQ was investigated in terms of factor structure, intersubscale correlations, frequency of endorsement and reported distress, reliability and validity, associations with traits of anxiety, depression and personality, and sex differences. Principal component analysis revealed a 6-component solution: paranoia, hallucinations, cognitive disorganization, grandiosity, anhedonia, and parent-rated negative symptoms. These components formed the basis of 6 subscales. Correlations between different experiences were low to moderate. All SPEQ subscales, except Grandiosity, correlated significantly with traits of anxiety, depression, and neuroticism. Scales showed good internal consistency, test-retest reliability, and convergent validity. Girls endorsed more paranoia, hallucinations, and cognitive disorganization; boys reported more grandiosity and anhedonia and had more parent-rated negative symptoms. As in adults at high risk for psychosis and with psychotic disorders, psychotic experiences in adolescents are characterized by multiple components. The study of psychotic experiences as distinct dimensional quantitative traits is likely to prove an important strategy for future research, and the SPEQ is a self- and parent-report questionnaire battery that embodies this approach.

Georgina M. Hosang, Alastair G. Cardno, Daniel Freeman, Angelica Ronald (2017)Characterization and structure of hypomania in a British nonclinical adolescent sample, In: Journal of affective disorders207pp. 228-235 Elsevier

Background: This study aimed to test the validity of using the Hypomania Checklist-16 [HCL-16] to measure hypomania in a British adolescent community sample. Limited research is available concerning the characterization of hypomania among community adolescent samples, particularly in the UK, despite it,: potential importance for early intervention policy development. Method: To explore the structure and characterization of hypomania in a British adolescent nonclinical cohort. over 1400 17 year olds (Mean=17.05 years; SD=0.88) completed the HCL-16 along with measures of different psychological and psychopathological dimensions. Results: Principal components analysis revealed a 2-component solution for the HCL-16, described as active elated and irritable/risk-taking. Hypomanic symptoms were significantly correlated with many psychopathological dimensions. There were distinct correlation patterns for the two HCL-16 subscales, with the irritability/ risk-taking subscale showing significantly stronger associations with psychotic-like experiences, internalizing and externalizing problems, and reduced life satisfaction relative to the active-elated dimension. Adolescents at `high-risk' for bipolar disorder reported more psychopathology relative to the comparison group. Limitations: Absence of the clinical diagnosis of bipolar disorder in the sample means that the classification of the 'high-risk' group cannot be confirmed. Conclusions: The structure of the HCL-16 in this UK adolescent sample mirrored that observed in adult and clinical cohorts. The observed links between the HCL-16 and psychopathological dimensions that have been previously associated with both hypomania and bipolar disorder lend support to the HCL-16's validity as a hypomania instrument for adolescents. Better understanding of hypomania prior to adulthood has considerable potential for informing early intervention approaches.

David Mason, Angelica Ronald, Antony Ambler, Avshalom Caspi, Renate Houts, Richie Poulton, Sandhya Ramrakha, Jasmin Wertz, Terrie E. Moffitt, Francesca Happe (2021)Autistic traits are associated with faster pace of aging: Evidence from the Dunedin study at age 45, In: Autism research14(8)pp. 1684-1694 Wiley

Growing evidence indicates that the defining characteristics of autism spectrum disorder (ASD) are distributed throughout the general population; hence, understanding the correlates of aging in people with high autistic traits could shed light on ASD and aging. 915 members of the Dunedin longitudinal birth cohort completed a measure of autistic traits at age 45. A composite measure of the "pace of aging" was derived by tracking the decline in 19 biomarkers across ages 26, 32, 38, and 45 years. Facial age was also assessed. Reports of perceived health were collected from participants themselves, informants, and interviewers. Higher self-reported autistic traits significantly correlated with a faster pace of aging, older facial age, and poorer self-, informant-, and interviewer-rated health. After control for sex, SES and IQ, autistic traits were significantly associated with each variable: pace of aging (beta = 0.09), facial age (beta = 0.08), self- (beta = -0.15), informant (beta = -0.12), and interviewer-rated (beta = -0.17) health. Autistic traits measured at age 45 are associated with faster aging. Participants with high autistic traits appear to be more vulnerable to poor health outcomes, as previously reported for those clinically diagnosed with ASD. Therefore, autistic traits may have important health implications. Replicating these findings in samples of autistic people is needed to identify the mechanism of their effect on aging and physical health to improve outcomes for those with ASD diagnoses or high autistic traits. Lay Summary The role that autistic traits have in relation to health outcomes has not been investigated. We looked at how physical health and aging (measured with self-reported questions and decline in multiple biological measures) were related to autistic traits (measured with a questionnaire, at age 45). We found that higher autistic traits were associated with poorer reports of physical health, and a faster pace of aging. This suggests that both those with autism and those with higher autistic traits may be more likely to experience poorer health outcomes.

Beata Tick, Emma Colvert, Fiona McEwen, Catherine Stewart, Emma Woodhouse, Nicola Gillan, Victoria Hallett, Stephanie Lietz, Tracy Garnett, Emily Simonoff, Angelica Ronald, Patrick Bolton, Francesca Happe, Fruehling Rijsdijk (2016)Autism Spectrum Disorders and Other Mental Health Problems: Exploring Etiological Overlaps and Phenotypic Causal Associations, In: Journal of the American Academy of Child and Adolescent Psychiatry55(2)pp. 106-113 Elsevier

Objective: Recent studies have highlighted the impact of coexisting mental health problems in autism spectrum disorders (ASD). No twin studies to date have reported on individuals meeting diagnostic criteria of ASD. This twin study reports on the etiological overlap between the diagnosis of ASD and emotional symptoms, hyperactivity, and conduct problems measured with the Strengths and Difficulties Questionnaire. Method: Genetic and environmental influences on the covariance between ASD and coexisting problems were estimated, in line with the correlated risks model prediction. Phenotypic causality models were also fitted to explore alternative explanations of comorbidity: namely, that coexisting problems are the result of or result in ASD symptoms; that they increase recognition of ASD; or that they arise due to an over-observation bias/confusion when differentiating between phenotypes. Results: More than 50% of twins with broad spectrum/ASD met the borderline/abnormal levels cut-off criteria for emotional symptoms or hyperactivity, and approximately 25% met these criteria for the 3 reported problems. In comparison, between 13% and 16% of unaffected twins scored above the cut-offs. The phenotypic correlation between ASD and emotional symptoms was explained entirely by genetic influences and accompanied by a moderate genetic correlation (0.42). The opposite was true for the overlap with conduct problems, as nonshared-environmental factors had the strongest impact. For hyperactivity, the best-fitting model suggested a unidirectional phenotypic influence of hyperactivity on ASD. Conclusion: Our findings suggest a possible effect of hyperactivity on identification of ASD. The lack of genetic influences on conduct problems ASD overlap further supports the genetic independence of these 2 phenotypes. Finally, the co-occurrence of emotional symptoms in ASD, compared to other co-occurring problems, is completely explained by common genetic effects.

Angelica Ronald, Rosa A. Hoekstra (2011)Autism Spectrum Disorders and Autistic Traits: A Decade of New Twin Studies, In: American journal of medical genetics. Part B, Neuropsychiatric genetics156B(3)pp. 255-274 Wiley

Researchers continue to pursue a better understanding of the symptoms, comorbidities, and causes of autism spectrum disorders. In this article we review more than 30 twin studies of autism spectrum disorders (ASDs) and autistic traits published in the last decade that have contributed to this endeavor. These twin studies have reported on the heritability of autism spectrum disorders and autistic traits in different populations and using different measurement and age groups. These studies have also stimulated debate and new hypotheses regarding why ASDs show substantial symptom heterogeneity, and what causes their comorbidity with intellectual disability, language delay, and other psychiatric disorders such as ADHD. These studies also reveal that the etiology of autism and autistic traits assessed in the general population is more similar than different, which contributes to the question of where the boundary lies between autism and typical development. Recent findings regarding molecular genetic and environmental causes of autism are discussed in the relation to these twin studies. Lastly, methodological assumptions of the twin design are given consideration, as well as issues of measurement. Future research directions are suggested to ensure that this decade is as productive as the last in attempting to disentangle the causes of autism spectrum disorders. (C) 2011 Wiley-Liss, Inc.

Sandra Gómez-Vallejo, Marguerite Leoni, Angelica Ronald, Emma Colvert, Francesca Happé, Patrick Bolton (2021)Autism spectrum disorder and obstetric optimality: a twin study and meta-analysis of sibling studies, In: Journal of child psychology and psychiatry62(11)pp. 1353-1362

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Recent studies have suggested that its aetiology is also influenced by environmental factors. Some of the most examined environmental factors are obstetric complications. However, the results are inconsistent. We aimed to explore the association between obstetric complications and autism in a population-based twin sample using the Obstetric Enquiry Scale (OES), a scale that measures the presence or absence of pre-, peri- and neonatal factors. Additionally, we report the meta-analytic results for obstetrical factors reported in previously published sibling studies. Our study included 115 cases pairs and 62 controls pairs and showed that children with autism and their unaffected co-twins present significantly more obstetric complications than controls (ASD vs. controls β 1.26, CI 95% 1.11-1.40 p 

Emma Colvert, Emily Simonoff, Simone J. Capp, Angelica Ronald, Patrick Bolton, Francesca Happe (2022)Autism Spectrum Disorder and Mental Health Problems: Patterns of Difficulties and Longitudinal Trajectories in a Population-Based Twin Sample, In: Journal of autism and developmental disorders52(3)pp. 1077-1091 Springer Nature

There is increasing concern regarding additional psychiatric problems that co-occur with Autism Spectrum Disorder (ASD), as reflected in recent changes to diagnostic schemes. However, there remains little research with population-based samples across childhood. We report on additional problems, as measured by the Strengths and Difficulties Questionnaire, in a population-based sample of 135 twins with ASD, 55 non-ASD co-twins, and 144 comparison twins low in ASD traits. Frequencies, associated demographic factors, and changes in mental health difficulties from age 4 to 13 years are presented. Our data confirm the high rates of additional difficulties reported in previous studies, and suggest that the profile, associated risk factors and longitudinal course of additional difficulties in ASD may differ from those in typically-developing populations.

Gregory L. Wallace, Clare Llewellyn, Alison Fildes, Angelica Ronald (2018)Autism spectrum disorder and food neophobia: clinical and subclinical links, In: The American journal of clinical nutrition108(4)pp. 701-707 Oxford Univ Press

Background: Autism spectrum disorder (ASD) has been linked with eating- and feeding-related atypicalities, including food neophobia (FN) (refusal to try unfamiliar foods), since its earliest description. Nevertheless, whether associations between ASD traits and FN extend subclinically into the broader population of children and their potential additive health impacts remains unexplored. Objective: We examined ASD-control group differences in FN and ASD trait-FN trait associations, as well as the ability of FN and autistic traits to predict one index of later health-related outcomes [body mass index (BMI)]. Design: Participants in the present study were a large community-based sample of 8- to 11-y-olds (n = 4564), including a relatively small group of children diagnosed with ASD (n = 37). Parents of these 8- to 11-y-old children completed assessments of FN and autistic traits and provided height and weight metrics at 12 y of age. Results: Children with ASD were rated as more food neophobic than their same-age non-ASD peers (2.67 +/- 0.83 compared with 2.22 +/- 0.73; P < 0.001), and there were subclinical associations between FN and ASD traits (social, communication, and restricted/repetitive behavior) in this community-based sample of children (P < 0.05). Moreover, whereas FN alone predicted lower BMI, the interaction of FN and ASD traits predicted higher BMI (P

H. Minnis, J. Reekie, D. Young, A. Gray, T. O'Connor, A. Ronald, R. Plomin (2007)Attachment disorders: an evolutionary perspective, In: British journal of psychiatry191(5)pp. 460-460 ROYAL COLLEGE OF PSYCHIATRISTS
Georgina M Hosang, Paul Lichtenstein, Angelica Ronald, Sebastian Lundström, Mark J Taylor, (2019)Association of Genetic and Environmental Risks for Attention-Deficit/Hyperactivity Disorder With Hypomanic Symptoms in Youths, In: JAMA psychiatry (Chicago, Ill.)76(11)pp. 1150-1158

Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder are highly comorbid, with significantly associated symptoms. The mechanisms that account for their co-occurrence are not known. To examine the degree to which genetic and environmental risk factors for ADHD traits, across childhood and adolescence, are associated with adolescent hypomanic symptoms. This study used data on 13 532 twin pairs from the Child and Adolescent Twin Study in Sweden, a prospective, longitudinal twin study. Their parents provided ADHD data when children were 9 or 12 years of age. Of those who reached 15 years of age, 3784 participated. Of those who reached 18 years of age, 3013 participated. The study was performed from December 20, 2017, to December 5, 2018. Data analysis was performed at the Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden, from March 1, 2018, to October 31, 2018. Attention-deficit/hyperactivity disorder traits and hypomanic symptoms were assessed using parent-rated instruments. Associations between ADHD and adolescent hypomanic symptoms across childhood and adolescence were investigated using generalized estimating equations. Multivariate twin models were used to examine the extent to which genetic and environmental risk factors for ADHD were associated with hypomania. Among 3784 15-year-old twin pairs and 3013 18-year-old twin pairs, ADHD and hypomanic symptoms were significantly associated (age 15 years: β = 0.30; 95% CI, 0.24-0.34; P 

Georgina M. Hosang, Joanna Martin, Robert Karlsson, Sebastian Lundstrom, Henrik Larsson, Angelica Ronald, Paul Lichtenstein, Mark J. Taylor, (2022)Association of Etiological Factors for Hypomanic Symptoms, Bipolar Disorder, and Other Severe Mental Illnesses, In: JAMA psychiatry (Chicago, Ill.)79(2)pp. 143-150 Amer Medical Assoc

IMPORTANCE Subsyndromal hypomanic symptoms are relatively common in the general population and are linked to the onset of bipolar disorder. Little is known about their etiology and whether this is shared with the etiology of bipolar disorder or other mental illnesses. OBJECTIVE To examine the genetic and environmental architecture of hypomanic symptoms in a nonclinical youth sample and compare estimates at varying severity levels and their association with diagnosed bipolar disorder. DESIGN, SETTING, AND PARTICIPANTS This cohort study used phenotypic and genetic data from the Child and Adolescent Twin Study in Sweden and included individuals with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis of psychiatric disorders from national registries for residents of Sweden. Associations between hypomania and polygenic risk scores for bipolar disorder, major depressive disorder and schizophrenia were also investigated. Analysis began November 2018 and ended October 2021. MAIN OUTCOMES AND MEASURES Hypomanic symptomswere assessed using the parent-rated Mood Disorders Questionnaire when the twins were aged 18 years. Bipolar disorder diagnosis and/or lithium prescription were ascertained from national registries for residents of Sweden. Polygenic risk scores for psychiatric disorders were calculated using independent discovery genetic data. RESULTS A total of 8568 twin pairs aged 18 years (9381 [54.7%] female) were included in the study. The hypomania heritability estimate was 59% (95% CI, 52%-64%) for male individuals and 29% (95% CI, 16%-44%) for female individuals. Unique environmental factors accounted for 41% (95% CI, 36%-47%) of the hypomania variance in male individuals and 45%(95% CI, 40%-50%) in female individuals. Shared environmental factors were only detected for female individuals and explained 26%(95% CI, 13%-38%) of the variance. The heritability estimates were fairly consistent across different hypomania severity groups. Moderate genetic (0.40; 95% CI, 0.21-0.58) and shared environmental (0.41; 95% CI, 0.03-0.75) correlations between hypomania and diagnosed bipolar disorder were found. Hypomania was significantly associated with the polygenic risk scores for schizophrenia (beta = 0.08; SE = 0.026; P =.002) and major depressive disorder (beta = 0.09; SE = 0.027; P =.001) but not bipolar disorder (beta = 0.017; SE = 0.03; P = 0.57) (bipolar disorder I [beta = 0.014; SE = 0.029; P =.64] or bipolar disorder II [beta = 0.045; SE = 0.027; P =.10]). CONCLUSIONS AND RELEVANCE Higher heritability for hypomania was found for male compared with female individuals. The results highlight the shared etiologies between hypomanic symptoms, bipolar disorder, major depression, and schizophrenia in youths. Future research should focus on identifying specific shared genetic and environmental factors. These findings support a possible dimensional model of bipolar disorder, with hypomania representing a continuous trait underlying the disorder.

Victoria Hallett, Angelica Ronald, Fruhling Rijsdijk, Francesca Happe (2010)Association of Autistic-Like and Internalizing Traits During Childhood: A Longitudinal Twin Study, In: The American journal of psychiatry167(7)pp. 809-817 American Psychiatric Association
Sania Shakoor, Helena M. S. Zavos, Claire M. A. Haworth, Phillip McGuire, Alastair G. Cardno, Daniel Freeman, Angelica Ronald (2016)Association between stressful life events and psychotic experiences in adolescence: evidence for gene-environment correlations, In: British journal of psychiatry208(6)pp. 532-538 Cambridge Univ Press

Background Stressful life events (SLEs) are associated with psychotic experiences. SLEs might act as an environmental risk factor, but may also share a genetic propensity with psychotic experiences. Aims To estimate the extent to which genetic and environmental factors influence the relationship between SLEs and psychotic experiences. Method Self-and parent reports from a community-based twin sample (4830 16-year-old pairs) were analysed using structural equation model fitting. Results SLEs correlated with positive psychotic experiences (r = 0.12-0.14, all P

R. A. Hoekstra, F. Happe, S. Baron-Cohen, A. Ronald (2009)Association between extreme autistic traits and intellectual disability: insights from a general population twin study, In: British journal of psychiatry195(6)pp. 531-536 Cambridge Univ Press

Background Autism is associated with intellectual disability. The strength and origin of this association is unclear. Aims To investigate the association between extreme autistic traits and intellectual disability in children from a community-based sample and to examine whether the association can be explained by genetic factors. Method Children scoring in the extreme 5% on measures of autistic traits, IQ and academic achievement were selected from 7965 7/8-year-old and 3687 9-year-old twin pairs. Phenotypic associations between extreme autistic traits and intellectual disability were compared with associations among the full-range scores. Genetic correlations were estimated using bivariate DeFries-Fulker extremes analyses. Results Extreme autistic traits were modestly related to intellectual disability; this association was driven by communication problems characteristic of autism. Although this association was largely explained by genetic factors, the genetic correlation between autistic traits and intellectual disability was only modest. Conclusions Extreme autistic traits are substantially genetically independent of intellectual disability.

B. St Pourcain, E. B. Robinson, V. Anttila, B. B. Sullivan, J. Maller, J. Golding, D. Skuse, S. Ring, D. M. Evans, S. Zammit, S. E. Fisher, B. M. Neale, R. J. L. Anney, S. Ripke, M. V. Hollegaard, T. Werge, A. Ronald, J. Grove, D. M. Hougaard, A. D. Borglum, P. B. Mortensen, M. J. Daly, G. Davey Smith (2018)ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties, In: Molecular psychiatry23(2)pp. 263-270 Springer Nature

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N. 5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2:34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.

Oliver Pain, Frank Dudbridge, Angelica Ronald (2018)Are your covariates under control? How normalization can reintroduce covariate effects, In: European journal of human genetics : EJHG26(8)pp. 1194-1201 Springer Nature

Many statistical tests rely on the assumption that the residuals of a model are normally distributed. Rank-based inverse normal transformation (INT) of the dependent variable is one of the most popular approaches to satisfy the normality assumption. When covariates are included in the analysis, a common approach is to first adjust for the covariates and then normalize the residuals. This study investigated the effect of regressing covariates against the dependent variable and then applying rank-based INT to the residuals. The correlation between the dependent variable and covariates at each stage of processing was assessed. An alternative approach was tested in which rank-based INT was applied to the dependent variable before regressing covariates. Analyses based on both simulated and real data examples demonstrated that applying rank-based INT to the dependent variable residuals after regressing out covariates re-introduces a linear correlation between the dependent variable and covariates, increasing type-I errors and reducing power. On the other hand, when rank-based INT was applied prior to controlling for covariate effects, residuals were normally distributed and linearly uncorrelated with covariates. This latter approach is therefore recommended in situations were normality of the dependent variable is required.

Dominika Sieradzka, Robert A. Power, Daniel Freeman, Alastair G. Cardno, Philip McGuire, Robert Plomin, Emma L. Meaburn, Frank Dudbridge, Angelica Ronald (2014)Are Genetic Risk Factors for Psychosis Also Associated with Dimension-Specific Psychotic Experiences in Adolescence?, In: PloS one9(4)pp. e94398-e94398 Public Library Science

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2, 152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value = 2.57x10(-4)) and rs9960767 (p-value = 6.23x10(-4)). Replication in an independent sample of 16-year-olds (N = 3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed.

Andrew J. O. Whitehouse, Martha Hickey, Angelica Ronald (2011)Are Autistic Traits in the General Population Stable across Development?, In: PloS one6(8)pp. e23029-e23029 Public Library Science

There is accumulating evidence that autistic traits (AT) are on a continuum in the general population, with clinical autism representing the extreme end of a quantitative distribution. While the nature and severity of symptoms in clinical autism are known to persist over time, no study has examined the long-term stability of AT among typically developing toddlers. The current investigation measured AT in 360 males and 400 males from the general population close to two decades apart, using the Pervasive Developmental Disorder subscale of the Child Behavior Checklist in early childhood (M = 2.14 years; SD = 0.15), and the Autism-Spectrum Quotient in early adulthood (M = 19.50 years; SD = 0.70). Items from each scale were further divided into social (difficulties with social interaction and communication) and non-social (restricted and repetitive behaviours and interests) AT. The association between child and adult measurements of AT as well the influence of potentially confounding sociodemographic, antenatal and obstetric variables were assessed using Pearson's correlations and linear regression. For males, Total AT in early childhood were positively correlated with total AT (r = .16, p = .002) and social AT (r = .16, p = .002) in adulthood. There was also a positive correlation for males between social AT measured in early childhood and Total (r = .17, p = .001) and social AT (r = .16, p = .002) measured in adulthood. Correlations for non-social AT did not achieve significance in males. Furthermore, there was no significant longitudinal association in AT observed for males or females. Despite the constraints of using different measures and different raters at the two ages, this study found modest developmental stability of social AT from early childhood to adulthood in boys.

Katharina Dworzynski, Angelica Ronald, Marianna Hayiou-Thomas, Frühling Rijsdijk, Francesca Happé, Patrick F. Bolton, Robert Plomin (2007)Aetiological relationship between language performance and autistic-like traits in childhood: a twin study, In: International journal of language & communication disorders42(3)pp. 273-292 Informa UK Ltd

Background: Impairments in language and communication are core features of autism spectrum disorders (ASDs). The basis for this association is poorly understood. How early language is related to each of the triad of impairments characteristic of ASDs is also in need of clarification. Aims: This is the first study that aims to determine the extent to which shared genetic and environmental factors underlie the association between early language performance and autistic-like traits (ALTs) in middle childhood. Methods & Procedures: Data came from a population-based twin sample (n = 6087 pairs) assessed prospectively at 2, 3, 4 and 8 years. ALTs measured by the Childhood Asperger Syndrome Test (CAST) at 8 years were investigated in relation to language assessed by the MacArthur Communicative Development Inventory (CDI) at 2, 3 and 4 years. Multivariate model fitting techniques were used to analyse the origins of this association. Outcomes & Results: Total CAST scores, as well as Social and Communication subscales, at 8 years were weakly but significantly negatively correlated with language ability at 2, 3 and 4 years. Correlations between language and restrictive and repetitive behaviours and interests (RRBI) were not significant. The phenotypic correlations between language and Social and Communication ALTs were almost entirely mediated by shared genetic influences. There were specific genetic influences on early language that were not shared with ALTs, and specific genetic influences on ALTs not shared with earlier language performance. Conclusions: This is the first study to demonstrate shared genetic influences in relation to language performance as an early antecedent of later ALTs. These results support the idea that the triad of core features in ALTs are aetiologically heterogeneous, with early language relating to social and communication impairments but not RRBIs.

Wikus Barkhuizen, Mark J. Taylor, Daniel Freeman, Angelica Ronald (2019)A Twin Study on the Association Between Psychotic Experiences and Tobacco Use During Adolescence, In: Journal of the American Academy of Child and Adolescent Psychiatry58(2)pp. 267-276.e8 Elsevier

Objective: Psychotic experiences (PE) are dimensional phenomena in the general population that resemble psychotic symptoms, such as paranoia and hallucinations. This is the first twin study to explore the degree to which tobacco use and PE share genetic or environmental influences. Previous studies on the association between adolescent tobacco use and PE have not considered PE dimensionally, included negative symptoms, or accounted for confounding by sleep disturbance and stressful life events. Method: An unselected adolescent twin sample (N = 3,787 pairs; mean age = 16.16 years) reported on PE (paranoia, hallucinations, cognitive disorganization, grandiosity, and anhedonia) and regularity of tobacco use. Parents rated the twins' negative symptoms. Regression analyses were conducted while adjusted for sociodemographic characteristics, prenatal maternal smoking, cannabis use, sleep disturbance, and stressful life events. Bivariate twin modeling was used to estimate the degree of genetic and common and unique environmental influences shared between tobacco use and PE. Results: Regular smokers were significantly more likely to experience paranoia, hallucinations, cognitive disorganization, and negative symptoms (beta = 0.17-0.34), but not grandiosity or anhedonia, than nonsmokers, after adjustment for confounders. Paranoia, hallucinations, and cognitive disorganization correlated >= 0.15 with tobacco use (r = 0.15-0.21, all p < .001). Significant genetic correlations (r(A) =0.37 -0.45) were found. Genetic influences accounted for most of the association between tobacco use and paranoia (84%) and cognitive disorganization (81%). Familial influences accounted for 80% of the association between tobacco use and hallucinations. Conclusion: Tobacco use and PE during adolescence were associated after adjustment for confounders. They appear to co-occur largely because of shared genetic influences.

A. Ronald, Henrik Larsson, H. Anckarsäter, P. Lichtenstein, (2011)A twin study of autism symptoms in Sweden, In: Molecular psychiatry16(10)pp. 1039-1047

This study aimed to identify empirically the number of factors underlying autism symptoms-social impairments, communication impairments, and restricted repetitive behaviors and interests-when assessed in a general population sample. It also investigated to what extent these autism symptoms are caused by the same or different genetic and environmental influences. Autistic symptoms were assessed in a population-based twin cohort of >12,000 (9- and 12-year-old) children by parental interviews. Confirmatory factor analyses, principal component analyses and multivariate structural equation model fitting were carried out. A multiple factor solution was suggested, with nearly all analyses pointing to a three-factor model for both boys and girls and at both ages. A common pathway twin model fit the data best, which showed that there were some underlying common genetic and environmental influences across the different autism dimensions, but also significant specific genetic effects on each symptom type. These results suggest that the autism triad consists of three partly independent dimensions when assessed in the general population, and that these different autism symptoms, to a considerable extent, have partly separate genetic influences. These findings may explain the large number of children who do not meet current criteria for autism but who show some autism symptoms. Molecular genetic research may benefit from taking a symptom-specific approach to finding genes associated with autism.

Angelica Ronald, Francesca Happe, Robert Plomin (2008)A twin study investigating the genetic and environmental aetiologies of parent, teacher and child ratings of autistic-like traits and their overlap, In: European child & adolescent psychiatry17(8)pp. 473-483 Springer Nature

In the present study we investigated phenotypic agreement between informants (parent, teacher and child self-report) on ratings of autistic-like traits and compared the genetic and environmental aetiologies of the informants' ratings and of their covariance. Parents and teachers of >2,500 pairs from a community twin sample completed an abbreviated Childhood Asperger Syndrome Test (CAST). The twins also completed an adapted self-report version of the CAST. Structural equation model-fitting was carried out. Correlations between raters were significant but moderate (0.16-0.33). The magnitude of heritability estimates of autistic-like traits varied across raters, being highest for parent-rated autistic-like traits (82-87%) and more modest for child self-reported autistic-like traits (36-47%). Genetic overlap was significant but moderate across all raters. These findings are discussed in relation to population screening for autism and future genetic research.

Sania Shakoor, Philip McGuire, Alastair G. Cardno, Daniel Freeman, Angelica Ronald (2018)A twin study exploring the association between childhood emotional and behaviour problems and specific psychotic experiences in a community sample of adolescents, In: Journal of child psychology and psychiatry59(5)pp. 565-573 Wiley

Background: Childhood emotional and behaviour problems are antecedents for later psychopathology. This study investigated genetic and environmental influences shaping the longitudinal association between childhood emotional and behaviour problems and specific PEs. Method: In a community-based twin sample, parents reported on emotional and behaviour problems when twins were ages 7 and 12 years. At age 16 years, specific PEs were measured using self-reports and parent reports. Structural equationmodel-fitting was conducted. Results: Childhood emotional and behaviour problems were significantly associated with paranoia, cognitive disorganisation and parent-rated negative symptoms in adolescence (mean r=.15-.38), and to a lesser extent with hallucinations, grandiosity and anhedonia (mean r=.04-.12). Genetic influences on childhood emotional and behaviour problems explained significant proportions of variance in adolescent paranoia (4%), cognitive disorganisation (8%) and parent-rated negative symptoms (3%). Unique environmental influences on childhood emotional and behaviour problems explained 1% of variance in PEs. Common environmental influences were only relevant for the relationship between childhood emotional and behaviour problems and parent-rated negative symptoms (explaining 28% of variance) and are partly due to correlated rater effects. Conclusions: Childhood emotional and behaviour problems are significantly, if weakly, associated with adolescent PEs. These associations are driven in part by common genetic influences underlying both emotional and behaviour problems and PEs. However, psychotic experiences in adolescence are largely influenced by genetic and environmental factors that are independent of general childhood emotional and behaviour problems, suggesting they are not merely an extension of childhood emotional and behaviour problems.

Elise B. Robinson, Karestan C. Koenen, Marie C. McCormick, Kerim Munir, Victoria Hallett, Francesca Happé, Robert Plomin, Angelica Ronald (2012)A multivariate twin study of autistic traits in 12-year-olds: testing the fractionable autism triad hypothesis, In: Behavior genetics42(2)pp. 245-255

Autistic traits—social impairment, communication impairment, and restricted and repetitive behaviors and interests—are heritable in the general population. Previous analyses have consistently reported limited genetic and environmental overlap between autistic trait domains in samples assessed in middle childhood. Here we extend this research to parent-report data for 12-year-olds. Data from 5,944 pairs in the Twins Early Development Study were analyzed to explore the domain-specific heritability and degree of shared genetic and environmental influences across different autistic traits in the general population and among individuals scoring in the top 5% of each domain. Sex differences in the etiological estimates were also tested in these analyses. Autistic traits were moderately to highly heritable (0.58–0.88) at age 12. Bivariate genetic correlations in the full sample (0.18–0.40) and the extremes (0.24–0.67), as well as even lower unique environmental correlations, all suggested considerable fractionation of genetic and environmental influences across autistic trait domains, in line with previous findings.

Agnieszka Gidziela, Yasmin I Ahmadzadeh, Giorgia Michelini, Andrea G Allegrini, Jessica Agnew-Blais, Lok Yan Lau, Megan Duret, Francesca Procopio, Emily Daly, Angelica Ronald, Kaili Rimfeld, Margherita Malanchini (2023)A meta-analysis of genetic effects associated with neurodevelopmental disorders and co-occurring conditions, In: Nature human behaviour

A systematic understanding of the aetiology of neurodevelopmental disorders (NDDs) and their co-occurrence with other conditions during childhood and adolescence remains incomplete. In the current meta-analysis, we synthesized the literature on (1) the contribution of genetic and environmental factors to NDDs, (2) the genetic and environmental overlap between different NDDs, and (3) the co-occurrence between NDDs and disruptive, impulse control and conduct disorders (DICCs). Searches were conducted across three platforms: Web of Science, Ovid Medline and Ovid Embase. Studies were included only if 75% or more of the sample consisted of children and/or adolescents and the studies had measured the aetiology of NDDs and DICCs using single-generation family designs or genomic methods. Studies that had selected participants on the basis of unrelated diagnoses or injuries were excluded. We performed multilevel, random-effects meta-analyses on 296 independent studies, including over four million (partly overlapping) individuals. We further explored developmental trajectories and the moderating roles of gender, measurement, geography and ancestry. We found all NDDs to be substantially heritable (family-based heritability, 0.66 (s.e. = 0.03); SNP heritability, 0.19 (s.e. = 0.03)). Meta-analytic genetic correlations between NDDs were moderate (grand family-based genetic correlation, 0.36 (s.e. = 0.12); grand SNP-based genetic correlation, 0.39 (s.e. = 0.19)) but differed substantially between pairs of disorders. The genetic overlap between NDDs and DICCs was strong (grand family-based genetic correlation, 0.62 (s.e. = 0.20)). While our work provides evidence to inform and potentially guide clinical and educational diagnostic procedures and practice, it also highlights the imbalance in the research effort that has characterized developmental genetics research.

Mark J. Taylor, Elise B. Robinson, Francesca Happe, Patrick Bolton, Daniel Freeman, Angelica Ronald (2015)A longitudinal twin study of the association between childhood autistic traits and psychotic experiences in adolescence, In: Molecular autism6(1)pp. 44-44 Springer Nature

Background: This twin study investigated whether autistic traits during childhood were associated with adolescent psychotic experiences. Methods: Data were collected from a community sample of approximately 5000 twin pairs, which included 32 individuals with diagnosed autism spectrum conditions (ASC). Parents rated autistic traits in the twins at four points between ages 8-16 years. Positive, negative, and cognitive psychotic experiences were assessed at age 16 years using self-and parent-report scales. Longitudinal twin analyses tested the associations between these measures. Results: Autistic traits correlated weakly or nonsignificantly with positive psychotic experiences (paranoia, hallucinations, and grandiosity), and modestly with cognitive psychotic experiences (cognitive disorganisation). Higher correlations were observed for parent-rated negative symptoms and self-reported anhedonia, although the proportion of variance in both accounted for by autistic traits was low (10 and 31 %, respectively). The majority of the genetic influences on negative symptoms and anhedonia were independent of autistic traits. Additionally, individuals with ASC displayed significantly more negative symptoms, anhedonia, and cognitive disorganisation than controls. Conclusions: Autistic traits do not appear to be strongly associated with psychotic experiences in adolescence; associations were also largely restricted to negative symptoms. Of note, the degree to which the genetic and environmental causes of autistic traits influenced psychotic experiences was limited. These findings thus support a phenotypic and etiological distinction between autistic traits and psychotic experiences.

Angelica Ronald, Lee M. Butcher, Sophia Docherty, Oliver S. P. Davis, Leonard C. Schalkwyk, Ian W. Craig, Robert Plomin (2010)A Genome-Wide Association Study of Social and Non-Social Autistic-Like Traits in the General Population Using Pooled DNA, 500 K SNP Microarrays and Both Community and Diagnosed Autism Replication Samples, In: Behavior genetics40(1)pp. 31-45 Springer US

Two separate genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with social and nonsocial autistic-like traits. We predicted that we would find SNPs associated with social and non-social autistic-like traits and that different SNPs would be associated with social and nonsocial. In Stage 1, each study screened for allele frequency differences in ~430,000 autosomal SNPs using pooled DNA on microarrays in high-scoring versus low-scoring boys from a general population sample ( N  = ~400/group). In Stage 2, 22 and 20 SNPs in the social and non-social studies, respectively, were tested for QTL association by individually genotyping an independent community sample of 1,400 boys. One SNP (rs11894053) was nominally associated ( P  

Lauren Micalizzi, Angelica Ronald, Kimberly J. Saudino (2016)A Genetically Informed Cross-Lagged Analysis of Autistic-Like Traits and Affective Problems in Early Childhood, In: Journal of abnormal child psychology44(5)pp. 937-947 Springer Nature

A genetically informed cross-lagged model was applied to twin data to explore etiological links between autistic-like traits and affective problems in early childhood. The sample comprised 310 same-sex twin pairs (143 monozygotic and 167 dizygotic; 53 % male). Autistic-like traits and affective problems were assessed at ages 2 and 3 using parent ratings. Both constructs were related within and across age (r = 0.30-0.53) and showed moderate stability (r = 0.45-0.54). Autistic-like traits and affective problems showed genetic and environmental influences at both ages. Whereas at age 2, the covariance between autistic-like traits and affective problems was entirely due to environmental influences (shared and nonshared), at age 3, genetic factors also contributed to the covariance between constructs. The stability paths, but not the cross-lagged paths, were significant, indicating that there is stability in both autistic-like traits and affective problems but they do not mutually influence each other across age. Stability effects were due to genetic, shared, and nonshared environmental influences. Substantial novel genetic and nonshared environmental influences emerge at age 3 and suggest change in the etiology of these constructs over time. During early childhood, autistic-like traits tend to occur alongside affective problems and partly overlapping genetic and environmental influences explain this association.

Angelica Ronald, Oliver Pain (2018)A systematic review of genome-wide research on psychotic experiences and negative symptom traits: new revelations and implications for psychiatry, In: Human molecular genetics27(R2)pp. R136-R152 Oxford University Press

Abstract We present a systematic review of genome-wide research on psychotic experience and negative symptom (PENS) traits in the community. We integrate these new findings, most of which have emerged over the last four years, with more established behaviour genetic and epidemiological research. The review includes the first genome-wide association studies of PENS, including a recent meta-analysis, and the first SNP heritability estimates. Sample sizes of 

Sania Shakoor, Phillip McGuire, Alastair G Cardno, Daniel Freeman, Robert Plomin, Angelica Ronald (2015)A shared genetic propensity underlies experiences of bullying victimization in late childhood and self-rated paranoid thinking in adolescence, In: Schizophrenia bulletin41(3)pp. 754-763

Bullying is a risk factor for developing psychotic experiences (PEs). Whether bullying is associated with particular PEs, and the extent to which genes and environments influence the association, are unknown. This study investigated which specific PEs in adolescence are associated with earlier bullying victimization and the genetic and environmental contributions underlying their association. Participants were 4826 twin pairs from a longitudinal community-based twin study in England and Wales who reported on their bullying victimization at the age of 12 years. Measures of specific PEs (self-rated Paranoia, Hallucinations, Cognitive disorganization, Grandiosity, Anhedonia, and parent-rated Negative Symptoms) were recorded at age of 16 years. Childhood bullying victimization was most strongly associated with Paranoia in adolescence (r = .26; P < .01), with weaker associations with Hallucinations, Cognitive Disorganization, parent-rated Negative Symptoms (r = .12-.20; P < .01), Grandiosity (r = .04; P < .05), and Anhedonia (r = .00, n.s.). Bivariate twin model-fitting demonstrated that bullying victimization and Paranoia were both heritable (35% and 52%, respectively) with unique environmental influences (39% and 48%, respectively), and bullying victimization showed common environmental influences (26%). The association between bullying victimization and Paranoia operated almost entirely via genetic influences (bivariate heritability = 93%), with considerable genetic overlap (genetic correlation = .55). In contrast to the assumed role of bullying victimization as an environmental trigger, these data suggest that bullying victimization in late childhood is particularly linked to self-rated Paranoia in adolescence via a shared genetic propensity. Clinically, individuals with a history of bullying victimization are predicted to be particularly susceptible to paranoid symptoms.

Angelica Ronald, Oliver Pain (2022)A Revolution Is Brewing in How We Understand the Shared Genetic Causes of Psychiatric Disorders, In: The American journal of psychiatry179(11)pp. 791-793
Victoria Hallett, Angelica Ronald, Fruhling Rijsdijk, Thalia C. Eley (2009)PHENOTYPIC AND GENETIC DIFFERENTIATION OF ANXIETY-RELATED BEHAVIORS IN MIDDLE CHILDHOOD, In: Depression and anxiety26(4)pp. 316-324 Wiley

Background: Anxiety-related behaviors (ARBs) are commonly observed during typical development, yet few studies have investigated their etiology in middle childhood. This study aimed, to examine both the phenotypic and genetic differentiation of ARB subtypes within the general population at age 7 and 9. It constituted a follow-zip to an earlier study of ARBs in preschool children. Methods: We investigated the phenotypic structure of ARBs in a large population-based twin sample, comprising 7,834 twin pairs at age 7 and 3,644 twin pairs at age 9. Quantitative genetic modeling techniques were then used to determine the relative influences of genetic and environmental factors upon different types of ARB and upon the covariation between them. Results: Factor analysis supported the presence of five ARB factors at both ages: negative cognitions, negative affect, few; obsessive-compulsive behaviors, and social anxiety. Multivariate genetic analyses revealed significant genetic effects and a small but significant influence of shared environment for all ARB subtypes. There was a moderate level of genetic specificity for each subtype as well as some shared genetic effects. Shared environmental influences correlated highly across all types of ARB, whereas nonshared environmental effects were largely subtype specific. Conclusions: The current results suggest that ARBs call be differentiated both phenotypically and genetically within middle childhood, with subtypes reflecting symptom. groupings of diagnosable disorders but also aspects of temperament. Although some etiological risk factors lead to a generalized vulnerability to anxiety, others may serve to differentiate between different types of ARBs. Depression and Anxiety 26:316-324, 2009. (c) 2009 Wiley-Liss, Inc.