Professor Malcolm von Schantz

Research Interests

My research focuses on circadian rhythms and sleep in humans and their molecular determinants.

Research Collaborations

In a multinational project together with colleagues at the University of São Paulo and the University of Chicago, I am studying sleep, circadian rhythms, and their relationships with health in the Baependi cohort, based in a small town in Minas Gerais, Brazil. In this unique study, we are able to study a wide variety of phenotypic traits, both molecular, physiological, neurobehavioural, and health outcome-related, and relate them to each other and to genotype.

Together with Fatima Labeed  and Rita Jabr and colleagues in Cambridge, I am studying circadian rhythms in human red blood cells. We are able to observe circadian rhythms in their electrophysiological properties and we are seeking to establish the molecular mechanism driving this, given that they have no nuclei and thus no gene expression.

Any paid vacancies within these projects will be advertised on Enquiries from self-funded PhD students may be considered at any time.


BMS1040 (Evolutionary origins of biodiversity)
BMS2036 (Molecular Biology and Genetics)
BMS2048 (Neuroscience)
BMS2062 (Animal Biology)
BMS3053 (Advanced topics in Molecular Biology)
BMS3066 (Biological rhythms)
VMS1008 (Structure & function)

Departmental Duties

I am the Senior PTY tutor responsible for international placements within the School of Bioscience and Medicine. Currently, placements are offered all across Europe through the Erasmus programme, as well as in North and South America, Asia, and Australia. The application cycle for these placements commences with a briefing at the start of the second year. I am also the Chair of the Level 5 Board of Examiners.


  • Special Visiting Scientist, University of São Paulo School of Medicine
  • Fellow of the Linnean Society
  • Member of the Society for Neuroscience, the European Sleep Research Society, and the Biochemical Society

Contact Me

Phone: 01483 68 6468

Find me on campus
Room: 08 AY 02


Journal articles

  • Gómez-Olivé F, Rohr J, Roden L, Rae D, von Schantz M. (2018) 'Associations between sleep parameters, non-communicable diseases, HIV status and medications in older, rural South Africans'. Nature Research Scientific Reports, 8 Article number 17321


    As part of the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI), we investigated sleep habits and their interactions with HIV or noncommunicable diseases (NCDs) in 5059 participants (median age: 61, interquartile range: 52—71, 54% females). Self-reported sleep duration was 8.2±1.6h, and bed and rise times were 20:48±1:15 and 05:31±1:05 respectively. Ratings of insufficient sleep were associated with older age, lack of formal education, unemployment, and obesity (p<0.05). Ratings of restless sleep were associated with being older, female, having more education, being unemployed, and single. Hypertension was associated with shorter self-reported sleep duration, poor sleep quality, restless sleep, and periods of stopping breathing during the night (p<0.05). HIV positive individuals not on antiretroviral treatment (ART) reported more nocturnal awakenings than those on ART (p=0.029) and HIV negative individuals (p=0.024), suggesting a negative net effect of untreated infection, but not of ART, on sleep quality. In this cohort, shorter, poor-quality sleep was associated with hypertension, but average self-reported sleep duration was longer than reported in other regions globally. It remains to be determined whether this is particular to this cohort, South Africa in general, or low- to middle-income countries undergoing transition.

  • Emmanuel P, von Schantz M. (2018) 'Absence of morningness alleles in non-European populations'. Taylor & Francis Chronobiology International,
    [ Status: Accepted ]


    In spite of suspected circadian differences between different ancestral groups, most human studies have used individuals of European descent. This also applies to three recent genome-wide association studies (GWAS), which pinpointed a number of chronotype loci. We investigated the distribution of these hits in different 1000 Genomes populations. We found six out of the 41 alleles previously identified by GWAS in European participants (in the genes RGS16, PER2, AK5, and between the genes APH1A and CA14) to be absent from some non-European population groups. This highlights the need for ancestral diversity in circadian research, and may reflect differences affecting the phenotype of individuals of East Asian ancestry.

  • Knutson K, von Schantz M. (2018) 'Associations between chronotype, morbidity and mortality in the UK Biobank cohort'. Taylor & Francis Chronobiology International, 35 (8), pp. 1045-1053.


    Later chronotype (i.e. evening preference) and later timing of sleep have been associated with greater morbidity, including higher rates of metabolic dysfunction and cardiovascular disease. However, no one has examined whether chronotype is associated with mortality risk to date. Our objective was to test the hypothesis that being an evening type is associated with increased mortality in a large cohort study, the UK Biobank. Our analysis included 433,268 adults aged 38-73 at the time of enrolment and an average 6.5- year follow-up. The primary exposure was chronotype, as assessed through a single self-reported question defining participants as definite morning types, moderate morning types, moderate evening types, or definite evening types. The primary outcomes were all-cause mortality and mortality due to cardiovascular disease (CVD). Prevalent disease was also compared among the chronotype groups. Analyses were adjusted for age, sex, ethnicity, smoking, body mass index, sleep duration, socioeconomic status and comorbidities. Greater eveningness, particularly being a definite evening type, was significantly associated with a higher prevalence of all comorbidities. Comparing definite evening type to definite morning type, the associations were strongest for psychological disorders (OR 1.94, 95% CI 1.86 to 2.02, p=<.001), followed by diabetes (OR 1.30, 95% CI 1.24 to 1.36, p=<.001), neurological disorders (OR 1.25, 95% CI 1.20 to 1.30, p=<.001), gastrointestinal/ abdominal disorders (OR 1.23, 95% CI 1.19 to 1.27, p=<.001), and respiratory disorders (OR 1.22, 95% CI 1.18 to 1.26, p=<.001). The total number of deaths was 10,534, out of which 2,127 were due to CVD. Greater eveningness, based on chronotype as an ordinal variable, was associated with a small increased risk of all-cause mortality (HR 1.02, 95% CI 1.004 to 1.05, p=.017) and CVD mortality (HR 1.04, 95% CI 1.00 to 1.09, p=.06). Compared to definite morning types, definite evening types had significantly increased risk of all-cause mortality (HR 1.10, 95% CI 1.02 to 1.18, p=.012). This first report of increased mortality in evening types is consistent with previous reports of increased levels of cardiometabolic risk factors in this group. Mortality risk in evening types may be due to behavioural, psychological, and physiological risk factors, many of which may be attributable to chronic misalignment between internal physiological timing and externally imposed timing of work and social activities. These findings suggest the need for researching possible interventions aimed at either modifying circadian rhythms in individuals or at allowing evening types greater working hour flexibility.

  • Henslee E, Crosby P, Kitcatt S, Parry J, Bernardini A, Abdallat R, Braun G, Fatoyinbo H, Harrison E, Edgar R, Hoettges K, Reddy A, Jabr R, von Schantz M, O’Neill J, Labeed F. (2017) 'Rhythmic potassium transport regulates the circadian clock in human red blood cells'. Nature Publishing Group Nature Communications, 8 Article number 1978(2017)


    Circadian rhythms organize many aspects of cell biology and physiology to a daily temporal program that depends on clock gene expression cycles in most mammalian cell types. However, circadian rhythms are also observed in isolated mammalian red blood cells (RBCs), which lack nuclei, suggesting the existence of post-translational cellular clock mechanisms in these cells. By using electrophysiological and pharmacological approaches, we show that human RBCs display circadian regulation of membrane conductance and cytoplasmic conductivity that depends on the cycling of cytoplasmic K+ levels. Using pharmacological intervention and ion replacement, we show that inhibition of K+ transport abolishes RBC electrophysiological rhythms. Our results suggest that in the absence of conventional transcription cycles, RBCs maintain a circadian rhythm in membrane electrophysiology through dynamic regulation of K+ transport.

  • Beale A, Pedrazzoli M, Gonçalves B, Beijamini F, Duarte N, Egan K, Knutson K, von Schantz M, Roden L. (2017) 'Comparison between an African town and a neighbouring village shows delayed, but not decreased, sleep during the early stages of urbanisation'. NATURE PUBLISHING GROUP Scientific Reports, 7 Article number 5697


    The well-established negative health outcomes of sleep deprivation, and the suggestion that availability of electricity may enable later bed times without compensating sleep extension in the morning, have stimulated interest in studying communities whose sleep pattern may resemble a preindustrial state. Here, we describe sleep and activity in two neighbouring communities, one urban (Milange) and one rural (Tengua), in a region of Mozambique where urbanisation is an ongoing process. The two communities differ in the amount and timing of daily activity and of light exposure, with later bedtimes (≈1 h) associated with more evening and less daytime light exposure seen in the town of Milange. In contrast to previous reports comparing communities with and without electricity, sleep duration did not differ between Milange (7.28 h) and Tengua (7.23 h). Notably, calculated sleep quality was significantly poorer in rural Tengua than in Milange, and poor sleep quality was associated with a number of attributes more characteristic of rural areas, including more intense physical labour and less comfortable sleeping arrangements. Thus, whilst our data support the hypothesis that access to electricity delays sleep timing, the higher sleep quality in the urban population also suggests that some aspects of industrialisation are beneficial to sleep.

  • Martynhak BJ, Hogben AL, Zanos P, Georgiou P, Andreatini R, Kitchen I, Archer SN, von Schantz M, Bailey A, Van Der Veen DR. (2017) 'Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3-/- mice, but not wildtype mice'. Nature Publishing Group Scientific Reports, 7 Article number 40399


    Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are ‘direct’ effects of light on affect, an ‘indirect’ pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3-/- mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3-/-) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3-/- mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3-/- nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3-/- phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light.

  • Egan K, Campos Santos H, Beijamini F, Duarte N, Horimoto A, Taporoski T, Vallada H, Negrão A, Krieger J, Pedrazzoli M, Knutson K, Pereira A, von Schantz M. (2017) 'Amerindian (but not African or European) ancestry is significantly associated with diurnal preference within an admixed Brazilian population'. Taylor & Francis Chronobiology International: the journal of biological and medical rhythm research, 34 (2), pp. 269-272.


    Significant questions remain unanswered regarding the genetic versus environmental contributions to racial/ethnic differences in sleep and circadian rhythms. We addressed this question by investigating the association between diurnal preference, using the Morningness-Eveningness questionnaire (MEQ), and genetic ancestry within the Baependi Heart Study cohort, a highly admixed Brazilian population based in a rural town. Analysis was performed using measures of ancestry, using the Admixture program, and MEQ from 1,453 individuals. We found an association between the degree of Amerindian (but not European of African) ancestry and morningness, equating to 0.16 units for each additional percent of Amerindian ancestry, after adjustment for age, sex, education, and residential zone. To our knowledge, this is the first published report identifying an association between genetic ancestry and MEQ, and above all, the first one based on ancestral contributions within individuals living in the same community. This previously unknown ancestral dimension of diurnal preference suggests a stratification between racial/ethnic groups in an as yet unknown number of genetic polymorphisms.

  • Beijamini F, Knutson K, Lorenzi-Filho G, Egan K, Taporoski T, De Paula L, Negrão A, Horimoto A, Duarte N, Vallada H, Krieger J, Pedrazzoli M, Pereira A, von Schantz M . (2016) 'Timing and quality of sleep in a rural Brazilian family-based cohort, the Baependi Heart Study'. Nature Publishing Group Scientific Reports, 6 Article number 39283 , pp. 1-9.


    Sleep is modulated by several factors, including sex, age, and chronotype. It has been hypothesised that contemporary urban populations are under pressure towards shorter sleep duration and poorer sleep quality. Baependi is a small town in Brazil that provides a window of opportunity to study the influence of sleep patterns in a highly admixed rural population with a conservative lifestyle. We evaluated sleep characteristics, excessive daytime sleepiness, and chronotype using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Morningness-Eveningness Questionnaire questionnaires, respectively. The sample consisted of 1,334 subjects from the Baependi Heart study (41.5% male; age: 46.5±16.2 y, range: 18—89 years). Average self-reported sleep duration was 07:07±01:31 (bedtime 22:32±01:27, wake up time: 06:17±01:25 hh:min), sleep quality score was 4.9+3.2, chronotype was 63.6±10.8 and daytime sleepiness was 7.4±4.8. Despite a shift towards morningness in the population, chronotype remained associated with reported actual sleep timing. Age and sex modulated the ontogeny of sleep and chronotype, increasing age was associated with earlier sleep time and shorter sleep duration. Women slept longer and later, and reported poorer sleep quality than men (p<0.0001). This study provides indirect evidence in support of the hypothesis that sleep timing was earlier prior to full urbanisation.

  • Egan KJ, von Schantz M, Negrão AB, Santos HC, Horimoto ARVR, Duarte NE, Gonçalves GC, Soler JMP, de Andrade M, Lorenzi-Filho G, Vallada H, Taporoski TP, Pedrazzoli M, Azambuja AP, de Oliveira CM, Alvim RO, Krieger JE, Pereira AC. (2016) 'Cohort profile: the Baependi Heart Study--a family-based, highly admixed cohort study in a rural Brazilian town'. BMJ Publishing Group BMJ Open, 6 (10) Article number e011598


    Purpose Cardiovascular disease (CVD) is a major challenge to global health. The same epidemiological transition scenario is replayed as countries develop, but with variations based on environment, culture and ethnic mixture. The Baependi Heart Study was set up in 2005 to develop a longitudinal family-based cohort study that reflects on some of the genetic and lifestyle-related peculiarities of the Brazilian populations, in order to evaluate genetic and environmental influences on CVD risk factor traits. Participants Probands were recruited in Baependi, a small rural town in the state of Minas Gerais, Brazil, following by first-degree and then increasingly more distant relatives. The first follow-up wave took place in 2010, and the second in 2016. At baseline, the study evaluated 1691 individuals across 95 families. Cross-sectional data have been collected for 2239 participants. Findings to date Environmental and lifestyle factors and measures relevant to cardiovascular health have been reported. Having expanded beyond cardiovascular health outcomes, the phenotype datasets now include genetics, biochemistry, anthropometry, mental health, sleep and circadian rhythms. Many of these have yielded heritability estimates, and a shared genetic background of anxiety and depression has recently been published. In spite of universal access to electricity, the population has been found to be strongly shifted towards morningness compared with metropolitan areas. Future plans A new follow-up, marking 10 years of the study, is ongoing in 2016, in which data are collected as in 2010 (with the exception of the neuropsychiatric protocol). In addition to this, a novel questionnaire package collecting information about intelligence, personality and spirituality is being planned. The data set on circadian rhythms and sleep will be amended through additional questionnaires, actimetry, home sleep EEG recording and dim light melatonin onset (DLMO) analysis. Finally, the anthropometric measures will be expanded by adding three-dimensional facial photography, voice recording and anatomical brain MRI.

  • Egan K, Knutson K, Pereira A, von Schantz M. (2016) 'The role of race and ethnicity in sleep, circadian rhythms and cardiovascular health'. Elsevier Sleep Medicine Reviews,


    In recent years, strong evidence has emerged suggesting that insufficient duration, quality, and/or timing of sleep are associated with cardiovascular disease (CVD), and various mechanisms for this association have been proposed. Such associations may be related to endophenotypic features of the sleep homeostat and the circadian oscillator, or may be state-like effects of the environment. Here, we review recent literature on sleep, circadian rhythms and CVD with a specific emphasis on differences between racial/ethnic groups. We discuss the reported differences, mainly between individuals of European and African descent, in parameters related to sleep (architecture, duration, quality) and circadian rhythms (period length and phase shifting). We further review racial/ethnic differences in cardiovascular disease and its risk factors, and develop the hypothesis that racial/ethnic health disparities may, to a greater or smaller degree, relate to differences in parameters related to sleep and circadian rhythms. When humans left Africa some 100,000 years ago, some genetic differences between different races/ethnicities were acquired. These genetic differences have been proposed as a possible predictor of CVD disparities, but concomitant differences in culture and lifestyle between different groups may equally explain CVD disparities. We discuss the evidence for genetic and environmental causes of these differences in sleep and circadian rhythms, and their usefulness as health intervention targets.

  • Taporoski TP, Negrao AB, Horimoto ARVR, Duarte NE, Alvim RO, de Oliveira CM, Krieger JE, von Schantz M, Vallada H, Pereira AC. (2015) 'Shared Genetic Factors of Anxiety and Depression Symptoms in a Brazilian Family-Based Cohort, the Baependi Heart Study'. PUBLIC LIBRARY SCIENCE PLOS ONE, 10 (12) Article number ARTN e0144255
  • von Schantz M, Taporoski TP, Horimoto AR, Duarte NE, Vallada H, Krieger JE, Pedrazzoli M, Negrão AB, Pereira AC. (2015) 'Distribution and heritability of diurnal preference (chronotype) in a rural Brazilian family-based cohort, the Baependi study.'. Nature Publishing Group Scientific Reports, 5 Article number 9214
  • Archer SN, Laing EE, Möller-Levet CS, van der Veen DR, Bucca G, Lazar AS, Santhi N, Slak A, Kabiljo R, von Schantz M, Smith CP, Dijk DJ. (2014) 'Mistimed sleep disrupts circadian regulation of the human transcriptome.'. Proc Natl Acad Sci U S A,


    Circadian organization of the mammalian transcriptome is achieved by rhythmic recruitment of key modifiers of chromatin structure and transcriptional and translational processes. These rhythmic processes, together with posttranslational modification, constitute circadian oscillators in the brain and peripheral tissues, which drive rhythms in physiology and behavior, including the sleep-wake cycle. In humans, sleep is normally timed to occur during the biological night, when body temperature is low and melatonin is synthesized. Desynchrony of sleep-wake timing and other circadian rhythms, such as occurs in shift work and jet lag, is associated with disruption of rhythmicity in physiology and endocrinology. However, to what extent mistimed sleep affects the molecular regulators of circadian rhythmicity remains to be established. Here, we show that mistimed sleep leads to a reduction of rhythmic transcripts in the human blood transcriptome from 6.4% at baseline to 1.0% during forced desynchrony of sleep and centrally driven circadian rhythms. Transcripts affected are key regulators of gene expression, including those associated with chromatin modification (methylases and acetylases), transcription (RNA polymerase II), translation (ribosomal proteins, initiation, and elongation factors), temperature-regulated transcription (cold inducible RNA-binding proteins), and core clock genes including CLOCK and ARNTL (BMAL1). We also estimated the separate contribution of sleep and circadian rhythmicity and found that the sleep-wake cycle coordinates the timing of transcription and translation in particular. The data show that mistimed sleep affects molecular processes at the core of circadian rhythm generation and imply that appropriate timing of sleep contributes significantly to the overall temporal organization of the human transcriptome.

  • Pereira DS, Van Der Veen DR, Gonçalves BSB, Tufik S, Von Schantz M, Archer SN, Pedrazzoli M. (2014) 'The effect of different photoperiods in circadian rhythms of Per3 knockout mice'. BioMed Research International, 2014


    The aim of this study was to analyse the circadian behavioural responses of mice carrying a functional knockout of the Per3 gene (P e r 3 - / -) to different light: dark (L: D) cycles. Male adult wild-type (WT) and P e r 3 - / - mice were kept under 12-hour light: 12-hour dark conditions (12L: 12D) and then transferred to either a short or long photoperiod and subsequently released into total darkness. All mice were exposed to both conditions, and behavioural activity data were acquired through running wheel activity and analysed for circadian characteristics during these conditions. We observed that, during the transition from 12L: 12D to 16L: 8D, P e r 3 - / - mice take approximately one additional day to synchronise to the new L: D cycle compared to WT mice. Under these long photoperiod conditions, P e r 3 - / - mice were more active in the light phase. Our results suggest that P e r 3 - / - mice are less sensitive to light. The data presented here provides further evidence that Per3 is involved in the suppression of behavioural activity in direct response to light. © 2014 D. S. Pereira et al.

  • Möller-Levet CS, Archer SN, Bucca G, Laing EE, Slak A, Kabiljo R, Lo JC, Santhi N, von Schantz M, Smith CP, Dijk DJ. (2013) 'Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome.'. Proc Natl Acad Sci U S A, United States: 110 (12), pp. E1132-E1141.


    Insufficient sleep and circadian rhythm disruption are associated with negative health outcomes, including obesity, cardiovascular disease, and cognitive impairment, but the mechanisms involved remain largely unexplored. Twenty-six participants were exposed to 1 wk of insufficient sleep (sleep-restriction condition 5.70 h, SEM = 0.03 sleep per 24 h) and 1 wk of sufficient sleep (control condition 8.50 h sleep, SEM = 0.11). Immediately following each condition, 10 whole-blood RNA samples were collected from each participant, while controlling for the effects of light, activity, and food, during a period of total sleep deprivation. Transcriptome analysis revealed that 711 genes were up- or down-regulated by insufficient sleep. Insufficient sleep also reduced the number of genes with a circadian expression profile from 1,855 to 1,481, reduced the circadian amplitude of these genes, and led to an increase in the number of genes that responded to subsequent total sleep deprivation from 122 to 856. Genes affected by insufficient sleep were associated with circadian rhythms (PER1, PER2, PER3, CRY2, CLOCK, NR1D1, NR1D2, RORA, DEC1, CSNK1E), sleep homeostasis (IL6, STAT3, KCNV2, CAMK2D), oxidative stress (PRDX2, PRDX5), and metabolism (SLC2A3, SLC2A5, GHRL, ABCA1). Biological processes affected included chromatin modification, gene-expression regulation, macromolecular metabolism, and inflammatory, immune and stress responses. Thus, insufficient sleep affects the human blood transcriptome, disrupts its circadian regulation, and intensifies the effects of acute total sleep deprivation. The identified biological processes may be involved with the negative effects of sleep loss on health, and highlight the interrelatedness of sleep homeostasis, circadian rhythmicity, and metabolism.

  • Lazar AS, Santhi N, Hasan S, Lo JC, Johnston JD, Von Schantz M, Archer SN, Dijk DJ. (2012) 'Circadian period and the timing of melatonin onset in men and women: predictors of sleep during the weekend and in the laboratory.'. J Sleep Res,
  • Lázár AS, Slak A, Lo JC, Santhi N, von Schantz M, Archer SN, Groeger JA, Dijk DJ. (2012) 'Sleep, diurnal preference, health, and psychological well-being: a prospective single-allelic-variation study.'. Chronobiol Int, England: 29 (2), pp. 131-146.
  • Hasan S, Santhi N, Lazar AS, Slak A, Lo J, von Schantz M, Archer SN, Johnston JD, Dijk DJ. (2012) 'Assessment of circadian rhythms in humans: comparison of real-time fibroblast reporter imaging with plasma melatonin.'. FASEB J,
  • Lo JC, Groeger JA, Santhi N, Arbon EL, Lazar AS, Hasan S, von Schantz M, Archer SN, Dijk DJ. (2012) 'Effects of partial and acute total sleep deprivation on performance across cognitive domains, individuals and circadian phase.'. PLoS One, United States: 7 (9)


    Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate.

  • Archer SN, Carpen JD, Gibson M, Lim GH, Johnston JD, Skene DJ, von Schantz M. (2010) 'Polymorphism in the PER3 Promoter Associates with Diurnal Preference and Delayed Sleep Phase Disorder'. AMER ACAD SLEEP MEDICINE SLEEP, 33 (5), pp. 695-701.


    Study Objectives: To screen the PER3 promoter for polymorphisms and investigate the phenotypic associations of these polymorphisms with diurnal preference, delayed sleep phase disorder/syndrome (DSPD/DSPS), and their effects on reporter gene expression. Design: Interspecific comparison was used to define the approximate extent of the PER3 promoter as the region between the transcriptional start site and nucleotide position −874. This region was screened in DNA pools using PCR and direct sequencing, which was also used to screen DNA from individual participants. The different promoter alleles were cloned into a luciferase expression vector and a deletion library created. Promoter activation was measured by chemiluminescence. Setting: N/A Patients or Participants: DNA samples were obtained from volunteers with defined diurnal preference (3 x 80, selected from a pool of 1,590), and DSPD patients (n = 23). Interventions: N/A Measurements and Results: We verified three single nucleotide polymorphisms (G −320T, C −319A, G −294A), and found a novel variable number tandem repeat (VNTR) polymorphism (−318 1/2 VNTR). The −320T and −319A alleles occurred more frequently in DSPD compared to morning (P = 0.042 for each) or evening types (P = 0.006 and 0.033). The allele combination TA2G was more prevalent in DSPD compared to morning (P = 0.033) or evening types (P = 0.002). Luciferase expression driven by the TA2G combination was greater than for the more common GC2A (P < 0.05) and the rarer TA1G (P < 0.001) combinations. Deletion reporter constructs identified two enhancer regions (−703 to −605, and −283 to −80). Conclusions: Polymorphisms in the PER3 promoter could affect its expression, leading to potential differences in the observed functions of PER3.

  • Ellis J, von Schantz M, Jones KHS, Archer SN. (2009) 'Association between Specific Diurnal Preference Questionnaire Items and PER3 VNTR Genotype'. TAYLOR & FRANCIS INC CHRONOBIOLOGY INTERNATIONAL, 26 (3) Article number PII 910356950 , pp. 464-473.
  • von Schantz M. (2008) 'Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters'. INDIAN ACAD SCIENCES JOURNAL OF GENETICS, 87 (5), pp. 513-519.
  • Groeger JA, Viola AU, Lo JCY, von Schantz M, Archer SN, Dijk D-J. (2008) 'Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism'. AMER ACAD SLEEP MEDICINE SLEEP, 31 (8), pp. 1159-1167.
  • Archer SN, Viola AU, Kyriakopoulou V, von Schantz M, Dijk DJ. (2008) 'Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes'. AMER ACAD SLEEP MEDICINE SLEEP, 31 (5), pp. 608-617.


    Study Objectives: Individual sleep timing differs and is governed partly by circadian oscillators, which may be assessed by hormonal markers, or by clock gene expression. Clock gene expression oscillates in peripheral tissues, including leukocytes. The study objective was to determine whether the endogenous phase of these rhythms, assessed in the absence of the sleep-wake and light-dark cycle, correlates with habitual sleep-wake timing. Design: Observational, cross-sectional. Setting: Home environment and Clinical Research Center. Participants: 24 healthy subjects aged 25.0 ± 3.5 (SD) years. Measurements: Actigraphy and sleep diaries were used to characterize sleep timing. Circadian rhythm phase and amplitude of plasma melatonin, cortisol, and BMAL1, PER2, and PER3 expression were assessed during a constant routine. Results: Circadian oscillations were more robust for PER3 than for BMAL1 or PER2. Average peak timings were 6:05 for PER3, 8:06 for PER2, 15:06 for BMAL1, 4:20 for melatonin, and 10:49 for cortisol. Individual sleep-wake timing correlated with the phases of melatonin and cortisol. Individual PER3 rhythms correlated significantly with sleep-wake timing and the timing of melatonin and cortisol, but those of PER2 and BMAL1 did not reach significance. The correlation between sleep timing and PER3 expression was stronger in individuals homozygous for the variant of the PER3 polymorphism that is associated with morningness. Conclusions: Individual phase differences in PER3 expression during a constant routine correlate with sleep timing during entrainment. PER3 expression in leukocytes represents a useful molecular marker of the circadian processes governing sleep-wake timing.

  • Viola AU, Archer SN, James LM, Groeger JA, Lo JCY, Skene DJ, von Schantz M, Dijk D-J. (2007) 'PER3 polymorphism predicts sleep structure and waking performance'. CELL PRESS CURRENT BIOLOGY, 17 (7), pp. 613-618.
  • Jones KHS, Ellis J, Von Schantz M, Skene DJ, Dijk D-J, Archer SN. (2007) 'Age-related change in the association between a polymorphism in the PER3 gene and preferred timing of sleep and waking activities'. BLACKWELL PUBLISHING JOURNAL OF SLEEP RESEARCH, 16 (1), pp. 12-16.
  • Hogben AL, Ellis J, Archer SN, von Schantz M. (2007) 'Conscientiousness is a predictor of diurnal preference.'. Chronobiol Int, United States: 24 (6), pp. 1249-1254.


    The relationship between diurnal preference, as measured by the Horne-Ostberg questionnaire, and quantifiable personality traits was investigated in 617 participants. A hierarchical multiple regression analysis demonstrated that out of the personality variables, conscientiousness was the single biggest predictor of diurnal preference (beta=0.246), after controlling for depression, sleep disorders, shift work, age, gender, and demographic characteristics. Morningness has previously been associated with physiological parameters of the circadian clock and with polymorphisms in circadian clock genes, suggesting the possibility that conscientiousness, too, may be linked to the same parameters.

  • von Schantz M, Jenkins A, Archer SN. (2006) 'Evolutionary history of the vertebrate Period genes'. SPRINGER JOURNAL OF MOLECULAR EVOLUTION, 62 (6), pp. 701-707.
  • Von Schantz M, Jenkins A, Archer SN. (2006) 'Evolutionary history of the vertebrate Period genes'. Journal of Molecular Evolution, 62 (6), pp. 701-707.
  • Carpen JD, von Schantz M, Smits M, Skene DJ, Archer SN. (2006) 'A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans'. SPRINGER TOKYO JOURNAL OF HUMAN GENETICS, 51 (12), pp. 1122-1125.
  • Nadkarni NA, Weale ME, von Schantz M, Thomas MG. (2005) 'Evolution of a length polymorphism in the human PER3 gene, a component of the circadian system'. SAGE PUBLICATIONS INC JOURNAL OF BIOLOGICAL RHYTHMS, 20 (6), pp. 490-499.
  • Jenkins A, Archer SN, von Schantz M. (2005) 'Expansion during primate radiation of a variable number tandem repeat in the coding region of the circadian clock gene Period3'. SAGE PUBLICATIONS LTD JOURNAL OF BIOLOGICAL RHYTHMS, 20 (5), pp. 470-472.
  • Carpen JD, Archer SN, Skene DJ, Smits M, von Schantz M. (2005) 'A single-nucleotide polymorphism in the 5 '-untranslated region of the hPER2 gene is associated with diurnal preference'. BLACKWELL PUBLISHING JOURNAL OF SLEEP RESEARCH, 14 (3), pp. 293-297.
  • Dijk DJ, von Schantz M. (2005) 'Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators'. SAGE PUBLICATIONS INC JOURNAL OF BIOLOGICAL RHYTHMS, 20 (4), pp. 279-290.
  • Archer SN, Ahuja P, Caffe R, Mikol C, Foster RG, van Veen T, von Schantz M. (2004) 'Absence of phosphoglucose isomerase-1 in retinal photoreceptor, pigment epithelium and Muller cells'. BLACKWELL PUBLISHING LTD EUROPEAN JOURNAL OF NEUROSCIENCE, 19 (11), pp. 2923-2930.
  • von Schantz M, Archer SN. (2003) 'Clocks, genes and sleep'. ROYAL SOC MEDICINE PRESS LTD JOURNAL OF THE ROYAL SOCIETY OF MEDICINE, 96 (10), pp. 486-489.
  • Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J, von Schantz M. (2003) 'A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference'. AMER ACAD SLEEP MEDICINE SLEEP, 26 (4), pp. 413-415.
  • Robilliard DL, Archer SN, Arendt J, Lockley SW, Hack LM, English J, Leger D, Smits MG, Williams A, Skene DJ, von Schantz M. (2002) 'The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects'. BLACKWELL PUBLISHING LTD JOURNAL OF SLEEP RESEARCH, 11 (4), pp. 305-312.
  • von Schantz M, Provencio I, Foster RG. (2000) 'Recent developments in circadian photoreception: More than meets the eye'. ASSOC RESEARCH VISION OPHTHALMOLOGY INC INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 41 (7), pp. 1605-1607.
  • Archer SN, Thompson S, Lucas RJ, Foster RG, von Schantz M. (2000) 'Analysis of differentially expressed genes in the wildtype and rd mouse retina by macroarray screening.'. ASSOC RESEARCH VISION OPHTHALMOLOGY INC INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 41 (4), pp. S27-S27.
  • Gao N, von Schantz M, Foster RG, Hardie J. (1999) 'The putative brain photoperiodic photoreceptors in the vetch aphid, Megoura viciae'. PERGAMON-ELSEVIER SCIENCE LTD JOURNAL OF INSECT PHYSIOLOGY, 45 (11), pp. 1011-1019.
  • von Schantz M, Lucas RJ, Foster RG. (1999) 'Circadian oscillation of photopigment transcript levels in the mouse retina'. ELSEVIER SCIENCE BV MOLECULAR BRAIN RESEARCH, 72 (1), pp. 108-114.
  • Freedman MS, Lucas RJ, Soni B, von Schantz M, Munoz M, David-Gray Z, Foster R. (1999) 'Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors'. AMER ASSOC ADVANCEMENT SCIENCE SCIENCE, 284 (5413), pp. 502-504.
  • von Schantz M. (1998) 'Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters'. Journal of Genetics, 87 (5), pp. 513-519.


    Circadian rhythms and sleep are two separate but intimately related processes. Circadian rhythms are generated through the precisely controlled, cyclic expression of a number of genes designated clock genes. Genetic variability in these genes has been associated with a number of phenotypic differences in circadian, but also in sleep parameters both in mouse models and in humans. Diurnal preferences, as determined by the self-reported Horne-Östberg questionnaire, has been associated with polymorphisms in the human genes CLOCK, PER1, PER2, and PER3. Circadian rhythms sleep disorders have also been associated with mutations and polymorphisms in clock genes, with the advanced type cosegrating in an autosomal dominant inheritance pattern with mutations in the genes PER2 and CSNK1D, and the delayed type associating without discernible Mendelian inheritance with polymorphisms in CLOCK and PER3. Several mouse models of clock gene null alleles have been demonstrated to have affected sleep homeostasis. Recent findings have shown that the variable number tandem polymorphism in PER3, previously linked to diurnal preference, has profound effects on sleep homeostasis and cognitive performance following sleep loss, confirming the close association between the processes of circadian rhythms and sleep on the genetic level.

  • Lockley SW, Skene DJ, Thapan K, English J, Ribeiro D, Haimov I, Hampton S, Middleton B, von Schantz M, Arendt J. (1998) 'Extraocular light exposure does not suppress plasma melatonin in humans'. ENDOCRINE SOC JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 83 (9), pp. 3369-3372.
  • von Schantz M, Szel A, van Veen T, Farber DB. (1998) 'Cloning of a cyclic GMP phosphodiesterase gamma subunit from the ground squirrel retina'. ELSEVIER SCIENCE BV MOLECULAR BRAIN RESEARCH, 54 (2), pp. 327-333.

Conference papers

  • Archer SN, Laing EE, Moller-Levet CS, van der Veen DR, Bucca G, Lazar AS, Lo JCY, Santhi N, Slak A, Kabiljo R, von Schantz M, Smith CP, Dijk DJ. (2014) 'Mistimed sleep disrupts the circadian regulation of the human transcriptome'. WILEY-BLACKWELL JOURNAL OF SLEEP RESEARCH, Tallinn, ESTONIA: 22nd Congress of the European-Sleep-Research-Society 23, pp. 15-15.
  • Lazar A, Santhi N, Lo J, Slak A, Hasan S, Von Schantz M, Archer S, Dijk D-J. (2012) 'The circadian and homeostatic regulation of sleep spindle activity: effect of the PER3 VNTR polymorphism'. WILEY-BLACKWELL JOURNAL OF SLEEP RESEARCH, Paris, FRANCE: 21st Congress of the European-Sleep-Research-Society 21, pp. 82-82.
  • Lo JC, Groeger JA, Santhi N, Arbon EL, Lazar AS, Hasan S, Von Schantz M, Archer SN, Dijk DJ. (2012) 'Effects of circadian phase and prior partial sleep deprivation on executive functions during total sleep deprivation are modulated by PER3 polymorphism'. WILEY-BLACKWELL JOURNAL OF SLEEP RESEARCH, Paris, FRANCE: 21st Congress of the European-Sleep-Research-Society 21, pp. 41-41.
  • Groeger JA, Lo JC, Santhi N, Arbon EL, Lazar A, Hasan S, Von Schantz M, Archer SN, Dijk DJ. (2012) ''Trait-like' susceptibility to sleep loss varies with circadian phase and the task used to index vulnerable-resilient sleep-deprived performance'. WILEY-BLACKWELL JOURNAL OF SLEEP RESEARCH, Paris, FRANCE: 21st Congress of the European-Sleep-Research-Society 21, pp. 36-37.
  • Groeger J, Lo J, Viola A, Von Schantz M, Archer S, Dijk D. (2007) 'PER3 polymorphism predictssusceptibility to sleep deprivation-induced impairment of early morning executive performance'. AMER ACADEMY SLEEP MEDICINE SLEEP, Minneapolis, MN: 21st Annual Meeting of the Association-Professional-Sleep-Societies 30, pp. A54-A54.
  • Archer S, Viola A, Von Schantz M, Dijk D. (2007) 'Endogenous circadian rhythm of PER3 RNA in human leucocytes: Association with sleep timing, melatonin rhythm, and PER3 genotype'. AMER ACADEMY SLEEP MEDICINE SLEEP, Minneapolis, MN: 21st Annual Meeting of the Association-Professional-Sleep-Societies 30, pp. A54-A55.
  • Jones KH, Ellis J, Von Schantz M, Skene DJ, Dijk D, Archer SN. (2006) 'Age-related change in the association between a variable number tandem repeat polymorphism in the (PER3) gene and preferred timing of sleep and waking activities'. BLACKWELL PUBLISHING JOURNAL OF SLEEP RESEARCH, Innsbruck, AUSTRIA: 18th Congress of the European-Sleep-Research-Society 15, pp. 97-98.
  • Viola AU, Archer SN, Groeger JA, Skene DJ, Von Schantz M, Dijk DJ. (2006) 'Polymorphism in the clock gene PER3 predicts sleep structure and EEG power spectra'. BLACKWELL PUBLISHING JOURNAL OF SLEEP RESEARCH, Innsbruck, AUSTRIA: 18th Congress of the European-Sleep-Research-Society 15, pp. 53-53.
  • Von Schantz M, Archer SN. (2006) 'Genetic aspects of delayed sleep phase syndrome (DSPS)'. BLACKWELL PUBLISHING JOURNAL OF SLEEP RESEARCH, Innsbruck, AUSTRIA: 18th Congress of the European-Sleep-Research-Society 15, pp. 5-5.
  • Archer S, Robillard D, Skene D, Smits M, Williams A, Arendt J, von Schantz M. (2003) 'A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference'. AMER ACADEMY SLEEP MEDICINE SLEEP, CHICAGO, ILLINOIS: 17th Annual Meeting of the Associated-Professional-Sleep-Societies 26, pp. A109-A109.
  • Ahuja P, Archer SN, van Veen T, von Schantz M. (2003) 'Neuroleukin/AMF is present around cones and in various spatially restricted cell types of the mouse retina'. ASSOC RESEARCH VISION OPHTHALMOLOGY INC INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, FT LAUDERDALE, FLORIDA: Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology 44, pp. U459-U459.
  • von Schantz M, Archer SN, Ahuja P, van Veen T. (2002) 'Identification of transcripts enriched in the inner retina by differential macroarray hybridization'. ASSOC RESEARCH VISION OPHTHALMOLOGY INC INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, FT LAUDERDALE, FLORIDA: Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology 43, pp. U321-U321.
  • Archer SN, Lucas RJ, Thompson S, Foster RG, von Schantz M. (2002) 'Identification of a novel retinal kinase with promoter elements affected by circadian clock proteins'. ASSOC RESEARCH VISION OPHTHALMOLOGY INC INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, FT LAUDERDALE, FLORIDA: Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology 43, pp. U308-U308.

Book chapters

  • von Schantz M. (2017) 'Natural variation in human clocks'. in (ed.) Natural Variation and Clocks 1st Edition. Academic Press (Elsevier) (99)


    Our own species has a diurnal activity pattern and an average circadian period of 24.2 hours. Exact determination of circadian period requires expensive and intrusive protocols, and investigators are therefore using chronotype questionnaires as a proxy quantitative measure. Both measures show a normal distribution suggestive of a polygenic trait. The genetic components of the 24-hour feedback loop that generates circadian rhythms within our cells have been mapped in detail, identifying a number of candidate genes which have been investigated for genetic polymorphisms relating to the phenotypic variance. Key in this mechanism is the inhibitory complex containing period and cryptochrome proteins and interacting protein kinases and ubiquitin ligases, and the stability of this complex is recognized as the major determinant of circadian periodicity. The identification of the causative mutations in familial circadian rhythms sleep disorders has shed additional light into this mechanism. Mutations in the negative feedback protein-encoding genes PER2 and CRY2 as well as the CSNK1D gene encoding casein kinase I delta have been shown to cause advanced sleep phase disorder, and a mutation in the CRY1 gene delayed sleep phase disorder. The candidate gene approach has also yielded a number of genetic associations with chronotype as determined by questionnaires. More recently, genome-wide association studies (GWAS) of chronotype have both confirmed associations with the candidate clock gene PER2 and identified a serious of novel genes associated with variability in circadian rhythmicity, which have yet to be explored. Whilst considerable progress has thus been made with mapping the phenotypic diversity in human circadian rhythms and the genomic variability that causes it, studies to date have been mostly focused on individuals of European descent, and there is a strong need for research on other populations.

  • Lockley S, Skene D, Thapan K, English J, Ribeiro D, von Schantz M, Arendt J. (1999) 'Extraocular light exposure does not suppress plasma melatonin in humans'. SPRINGER , pp. 403-406.


  • von Schantz M, Skene DJ. (2015) Telling biological time from a blood sample - current capabilities and future potential. in (ed.) Annals of Clinical Biochestry SAGE

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