Professor Inga Prokopenko


Professor e-One Health and Head of Statistical Multi-Omics

Supervision

Postgraduate research supervision

My publications

Publications

Alexey Rayevsky, Dmytro Sirokha, Dariia Samofalova, Dmytro Lozhko, Olexandra Gorodna, Liudmyla Livshits (2021)Functional Effects In Silico Prediction for Androgen Receptor Ligand-Binding Domain Novel I836S Mutation, In: Life (Basel)11(7) MDPI

Over 1000 mutations are described in the androgen receptor (AR) gene. Of those, about 600 were found in androgen insensitivity syndrome (AIS) patients, among which 400 mutations affect the ligand-binding domain (LBD) of the AR protein. Recently, we reported a novel missense mutation c.2507T>G I836S (ClinVarID: 974911) in a patient with complete AIS (CAIS) phenotype. In the present study, we applied a set of computational approaches for the structural analysis of the ligand-binding domains in a wild-type and mutant AR to evaluate the functional impact of the novel I836S mutation. We revealed that the novel I836S substitution leads to a shorter existence time of the ligand’s gating tunnel and internal cavity, occurring only in the presence of S836 phosphorylation. Additionally, the analysis of phosphorylation of the 836 mutant residues explained the negative impact on AR homodimerization, since monomer surface changes indirectly impacted the binding site. Our analyses provide evidence that I836S causes disruptions of AR protein functionality and development of CAIS clinical features in patients.

P Parmar, Estelle Lowry, Florianne Vehmeijer, Hanan El Marroun, Alex Lewin, Mimmi Tolvanen, Evangelia Tzala, Leena Ala-Mursula, Karl-Heinz Herzig, Jouko Miettunen, Nina Rautio, Vincent W.V Jaddoe, Marjo-Riitta Jarvelin, Janine F. Felix, Sylvain Sebert (2020)Understanding the cumulative risk of maternal prenatal biopsychosocial factors on birth weight: a DynaHEALTH study on two birth cohorts, In: Journal of Epidemiology and Community Health74pp. 933-941

Background: There are various maternal prenatal biopsychosocial (BPS) predictors of birth weight, making it difficult to quantify their cumulative relationship. Methods: We studied two birth cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) born in 1985–1986 and the Generation R Study (from the Netherlands) born in 2002–2006. In NFBC1986, we selected variables depicting BPS exposure in association with birth weight and performed factor analysis to derive latent constructs representing the relationship between these variables. In Generation R, the same factors were generated weighted by loadings of NFBC1986. Factor scores from each factor were then allocated into tertiles and added together to calculate a cumulative BPS score. In all cases, we used regression analyses to explore the relationship with birth weight corrected for sex and gestational age and additionally adjusted for other factors. Results: Factor analysis supported a four-factor structure, labelled closely to represent their characteristics as ‘Factor1-BMI’ (body mass index), ‘Factor2-DBP’ (diastolic blood pressure), ‘Factor3-Socioeconomic-Obstetric-Profile’ and ‘Factor4-Parental-Lifestyle’. In both cohorts, ‘Factor1-BMI’ was positively associated with birth weight, whereas other factors showed negative association. ‘Factor3-Socioeconomic-Obstetric-Profile’ and ‘Factor4-Parental-Lifestyle’ had the greatest effect size, explaining 30% of the variation in birth weight. Associations of the factors with birth weight were largely driven by ‘Factor1-BMI’. Graded decrease in birth weight was observed with increasing cumulative BPS score, jointly evaluating four factors in both cohorts. Conclusion: Our study is a proof of concept for maternal prenatal BPS hypothesis, highlighting the components snowball effect on birth weight in two different European birth cohorts.

Christopher Hübel, Héléna A Gaspar, Jonathan R I Coleman, Ken B Hanscombe, Kirstin Purves, Mariaelisa Graff, Julius S Ngwa, Tsegaselassie Workalemahu, Paul O'Reilly, Cynthia M Bulik, Gerome Breen (2019)Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent, In: Nature communications105765 Nature Research

Body composition is often altered in psychiatric disorders. Using genome-wide common genetic variation data, we calculate sex-specific genetic correlations amongst body fat %, fat mass, fat-free mass, physical activity, glycemic traits and 17 psychiatric traits (up to N = 217,568). Two patterns emerge: (1) anorexia nervosa, schizophrenia, obsessive-compulsive disorder, and education years are negatively genetically correlated with body fat % and fat-free mass, whereas (2) attention-deficit/hyperactivity disorder (ADHD), alcohol dependence, insomnia, and heavy smoking are positively correlated. Anorexia nervosa shows a stronger genetic correlation with body fat % in females, whereas education years is more strongly correlated with fat mass in males. Education years and ADHD show genetic overlap with childhood obesity. Mendelian randomization identifies schizophrenia, anorexia nervosa, and higher education as causal for decreased fat mass, with higher body fat % possibly being a causal risk factor for ADHD and heavy smoking. These results suggest new possibilities for targeted preventive strategies.

ANNA ULRICH, Pablo Otero-Núñez, John Wharton, Emilia M Swietlik, Stefan Gräf, N Morrell, D Wang, Allan Lawrie, Martin R Wilkins, Christopher J Rhodes (2020)Expression Quantitative Trait Locus Mapping in Pulmonary Arterial Hypertension, In: Genes11(11)1247 MDPI

Expression quantitative trait loci (eQTL) can provide a link between disease susceptibility variants discovered by genetic association studies and biology. To date, eQTL mapping studies have been primarily conducted in healthy individuals from population-based cohorts. Genetic effects have been known to be context-specific and vary with changing environmental stimuli. We conducted a transcriptome- and genome-wide eQTL mapping study in a cohort of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) using RNA sequencing (RNAseq) data from whole blood. We sought confirmation from three published population-based eQTL studies, including the GTEx Project, and followed up potentially novel eQTL not observed in the general population. In total, we identified 2314 eQTL of which 90% were cis-acting and 75% were confirmed by at least one of the published studies. While we observed a higher GWAS trait colocalization rate among confirmed eQTL, colocalisation rate of novel eQTL reported for lung-related phenotypes was twice as high as that of confirmed eQTL. Functional enrichment analysis of genes with novel eQTL in PAH highlighted immune-related processes, a suspected contributor to PAH. These potentially novel eQTL specific to or active in PAH could be useful in understanding genetic risk factors for other diseases that share common mechanisms with PAH.

James Dooley, V Lagou, Jermaine Goveia, ANNA ULRICH, Katerina Rohlenova, Nathalie Heirman, Tobias Karakach, Yulia Lampi, Shawez Khan, Jun Wang, Tom Dresselaers, Uwe Himmelreich, Marc J Gunter, P Carmeliet, AJ Liston (2020)Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility, In: Cell Reports32(2)107880 Cell Press

Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. Known risk factors include obesity, diet, and type 2 diabetes; however, the low incidence rate and interconnection of these factors confound the isolation of individual effects. Here, we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the effects of obesity, diet, and diabetes on pancreatic cancer. Through longitudinal monitoring and multi-omics analysis in mice, we found distinct effects of protein, sugar, and fat dietary components, with dietary sugars increasing Mad2l1 expression and tumor proliferation. Using epidemiological approaches in humans, we find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure. [Display omitted] •Distinct roles for dietary fat, protein, and sugar on murine pancreatic cancer•Dietary glucose triggers Mad2l1 upregulation and tumor cell proliferation in mice•Gene-diet interaction identifies sugar-MAD2L1 link in human pancreatic cancer•Dietary plant fats were protective in human pancreatic cancer susceptibility Dooley et al. used parallel analysis of a murine pancreatic cancer model and a human prospective cohort to study the interaction of diet and pancreatic cancer. Both systems identify complex effects with different dietary components, converging on a link between dietary sugar and the cell-cycle checkpoint gene MAD2L1.

Eleni M Loizidou, Anastasia Kucherenko, Pavlo Tatarskyy, Sergey Chernushyn, Ganna Livshyts, Roman Gulkovskyi, Iryna Vorobiova, Yurii Antipkin, Oleksandra Gorodna, MARIKA KAAKINEN, Ludmila Livshits (2021)Risk of Recurrent Pregnancy Loss in the Ukrainian Population Using a Combined Effect of Genetic Variants: A Case-Control Study, In: Genes12(1)64 MDPI

We assessed the predictive ability of a combined genetic variant panel for the risk of recurrent pregnancy loss (RPL) through a case-control study. Our study sample was from Ukraine and included 114 cases with idiopathic RPL and 106 controls without any pregnancy losses/complications and with at least one healthy child. We genotyped variants within 12 genetic loci reflecting the main biological pathways involved in pregnancy maintenance: blood coagulation (F2, F5, F7, GP1A), hormonal regulation (ESR1, ADRB2), endometrium and placental function (ENOS, ACE), folate metabolism (MTHFR) and inflammatory response (IL6, IL8, IL10). We showed that a genetic risk score (GRS) calculated from the 12 variants was associated with an increased risk of RPL (odds ratio 1.56, 95% CI: 1.21, 2.04, p = 8.7 × 10−4). The receiver operator characteristic (ROC) analysis resulted in an area under the curve (AUC) of 0.64 (95% CI: 0.57, 0.72), indicating an improved ability of the GRS to classify women with and without RPL. Ιmplementation of the GRS approach can help define women at higher risk of complex multifactorial conditions such as RPL. Future well-powered genome-wide association studies will help in dissecting biological pathways previously unknown for RPL and further improve the identification of women with RPL susceptibility.

V Lagou, Reedik Magi, JJ Hottenga, Harald Grallert, John R. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, R Jansen, JL Min, AS Dimas, ANNA ULRICH, LIUDMILA ZUDINA, Jesper R Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G Stathopoulou, Aaron Isaacs, SM Willems, Pau Navarro, T Tanaka, Anne U Jackson, May E Montasser, Jeff R O'Connell, Lawrence F Bielak, R. Webster, Richa Saxena, Jeanette M Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, SY Shin, Najaf Amin, Albert V Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C D Johnson, T Johnson, Karen Kapur, G Thorleifsson, RJ Strawbridge, Laura J Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, T Fall, Ross M Fraser, A Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, ME Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, J Luan, Momoko Horikoshi, Ping An, S Sanna, Yvonne Boettcher, NW Rayner, Ilja M Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D Hastie, SH Wild, Stela McLachlan, SS Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, G Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, A Hicks, Rainer Rauramaa, S Bandinelli, B Thorand, Yongmei Liu, Iva Miljkovic, L Lind, Alex Doney, M Perola, AD Hingorani, M Kivimäki, Meena Kumari, Amanda J Bennett, C Groves, C Herder, Heikki A Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J L Bakker, Matti Uusitupa, Colin N. A Palmer, J Wouter Jukema, N Sattar, A Pouta, H Snieder, E Boerwinkle, James S Pankow, PK Magnusson, Ulrika Krus, Chiara Scapoli, Eco J C N de Geus, Matthias Blüher, Bruce H R Wolffenbuttel, Michael A Province, G Abecasis, James B Meigs, G Kees Hovingh, Jaana Lindström, James F Wilson, Alan F Wright, GV Dedoussis, Stefan R Bornstein, Peter E H Schwarz, Anke Tönjes, BR Winkelmann, B Boehm, W März, Andres Metspalu, Jackie F Price, P Deloukas, Antje Körner, Timo A. Lakka, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Richard N Bergman, J Tuomilehto, N Wareham, Claudia Langenberg, S Männistö, Paul Franks, C Hayward, Veronique Vitart, J Kaprio, Sophie Visvikis-Siest, Beverley Balkau, D Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia van Duijn, C Gieger, T Illig, L Ferrucci, NL Pedersen, Peter P Pramstaller, Michael Boehnke, Timothy M. Frayling, AR Shuldiner, Patricia A Peyser, Sharon L R Kardia, Lyle J. Palmer, BW Penninx, Pierre Meneton, T Harris, G Navis, Pim van der Harst, George Davey Smith, NG Forouhi, Ruth J F Loos, V Salomaa, N Soranzo, D Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, V Gudnason, DS Siscovick, H Watkins, Cecile Lecoeur, P Vollenweider, A Franco-Cereceda, P Eriksson, Marjo-Riitta Jarvelin, K Stefansson, A Hamsten, G Nicholson, Fredrik Karpe, ET Dermitzakis, C Lindgren, MI McCarthy, P Froguel, MARIKA KAAKINEN, VG Lyssenko, R Watanabe, E Ingelsson, Jose C Florez, J Dupuis, I Barroso, AP Morris, INGA PROKOPENKO (2021)Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability, In: Nature Communications1224 Nature Research

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

Gentaro Miyakawa, Bang Zheng, Jani Heikkinen, Daniela Petrova Quayle, Chinedu Udeh-Momoh, Annique Claringbould, Juliane Neumann, Hazal Haytural, MARIKA KAAKINEN, Elena Loizidou, EM Meissner, Lars Bertram, Djordje O Gveric, Steve M Gentleman, Johannes Attems, Robert Perneczky, Thomas Arzberger, Pierandrea Muglia, Christina M Lill, Laura Parkkinen, Lefkos T Middleton (2019)Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants, In: Alzheimer's and Dementia: Translational Research and Clinical Interventions5(1)pp. 814-824 Wiley Open Access

Introduction The role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Methods We dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls. Results TOMM40-L/APOE-ε4 alleles were associated with DLB (ORTOMM40-L = 3.61; P value = 3.23 × 10−9; ORAPOE-ε4 = 3.75; P value = 4.90 × 10−10) and earlier age at onset of DLB (HRTOMM40-L = 1.33, P value = .031; HRAPOE-ε4 = 1.46, P value = .004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (ORTOMM40-L = 4.40, P value = 1.15 × 10−6; ORAPOE-ε4 = 5.65, P value = 2.97 × 10−8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10−99; ORDLB+AD = 5.36, P value = 1.56 × 10−47). Discussion APOE-ε4/TOMM40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.

Arie Nouwen, Sonya S. Deschênes, Zhanna Balkhiyarova, Juan R Albertorio-Díaz, INGA PROKOPENKO, Norbert Schmitz (2021)Measurement invariance testing of the patient health questionnaire-9 (PHQ-9) across people with and without diabetes mellitus from the NHANES, EMHS and UK Biobank datasets, In: Journal of Affective Disorders292pp. 311-318 Elsevier B.V

Background The prevalence of depression is higher among those with diabetes than in the general population. The Patient Health Questionnaire (PHQ-9) is commonly used to assess depression in people with diabetes, but measurement invariance of the PHQ-9 across groups of people with and without diabetes has not yet been investigated. Methods Data from three independent cohorts from the USA (n=1,886 with diabetes, n=4,153 without diabetes), Quebec, Canada (n= 800 with diabetes, n= 2,411 without diabetes), and the UK (n=4,981 with diabetes, n=145,570 without diabetes), were used to examine measurement invariance between adults with and without diabetes. A series of multiple group confirmatory factor analyses were performed, with increasingly stringent model constraints applied to assess configural, equal thresholds, and equal thresholds and loadings invariance, respectively. One-factor and two-factor (somatic and cognitive-affective items) models were examined. Results Results demonstrated that the most stringent models, testing equal loadings and thresholds, had satisfactory model fit in the three cohorts for one-factor models (RMSEA = .063 or below and CFI = .978 or above) and two-factor models (RMSEA = .042 or below and CFI = .989 or above). Limitations Data were from Western countries only and we could not distinguish between type of diabetes. Conclusions Results provide support for measurement invariance between groups of people with and without diabetes, using either a one-factor or a two-factor model. While the two-factor solution has a slightly better fit, the one-factor solution is more parsimonious. Depending on research or clinical needs, both factor structures can be used.

Yanina R Timasheva, Zhanna Balkhiyarova, Timur R Nasibullin, Diana Sh Avzaletdinova, Tatiana V Morugova, Olga E Mustafina, INGA PROKOPENKO (2019)Multilocus associations of inflammatory genes with the risk of type 1 diabetes, In: Gene707pp. 1-8 Elsevier B.V

Background Genome-wide association studies have captured a large proportion of genetic variation related to type 1 diabetes mellitus (T1D). However, most of these studies are performed in populations of European ancestry and therefore the disease risk estimations can be inaccurate when extrapolated to other world populations. Methods We conducted a case-control study in 1866 individuals from the three major populations of the Republic of Bashkortostan (Russians, Tatars, and Bashkirs) in Russian Federation, using single-locus and multilocus approach to identify genetic predictors of T1D. Results We found that LTA rs909253 and TNF rs1800629 polymorphisms were associated with T1D in the group of Tatars. Meta-analysis of the association study results in the three ethnic groups has confirmed the association between the T1D risk and LTA rs909253 genetic variant. LTA rs909253 and TNF rs1800629 loci were also featured in combinations most significantly associated with T1D. Conclusion Our findings suggest that LTA rs909253 and TNF rs1800629 polymorphisms are associated with the risk of T1D both independently and in combination with polymorphic markers in other inflammatory genes, and the analysis of multi-allelic combinations provides valuable insight in the study of polygenic traits.

Alexessander Da Silva Couto Alves, N. Maneka G. De Silva, Ville Karhunen, Ulla Sovio, Shikta Das, H. Rob Taal, Nicole M. Warrington, Alexandra M. Lewin, Marika Kaakinen, Diana L. Cousminer, Elisabeth Thiering, Nicholas J. Timpson, Tom A. Bond, Estelle Lowry, Christopher D. Brown, Xavier Estivill, Virpi Lindi, Jonathan P. Bradfield, Frank Geller, Doug Speed, Lachlan J. M. Coin, Marie Loh, Sheila J. Barton, Lawrence J. Beilin, Hans Bisgaard, Klaus Bonnelykke, Rohia Alili, Ida J. Hatoum, Katharina Schramm, Rufus Cartwright, Marie-Aline Charles, Vincenzo Salerno, Karine Clement, Annique A.J Claringbould, BIOS Consortium, Cornelia M. van Duijin, Elena Moltchanova, Johan G. Eriksson, Cathy Elks, Bjarke Feenstra, Claudia Flexeder, Stephen Franks, Timothy M. Frayling, Rachel M. Freathy, Paul Elliot, Elisabeth Widen, Hakon Hakonarson, Andrew T. Hattersley, Alina Rodriguez, Marco Banterle, Joachim Heinrich, Barbara Heude, John W. Holloway, Albert Hofman, Elina Hypponen, Hazel Inskip, Lee M. Kaplan, Asa K. Hedman, Esa Laara, Holger Prokisch, Harald Grallert, Timo A. Lakka, Debbie A. Lawlor, Mads Melbye, Tarunveer S. Ahluwalia, Marcella Marinelli, Iona Y. Millwood, Lyle J. Palmer, Craig E. Pennell, John R. Perry, Susan M. Ring, Markku J. Savolainen, Fernando Rivadeneira, Marie Standl, Jordi Sunyer, Carla M.T Tiesler, Andre G. Uitterlinden, William Schierding, Justin M. O'Sullivan, Inga Prokopenko, Karl-Heinz Herzig, George Davey Smith, Paul O'Reilly, Janine F. Felix, Jessica L. Buxton, Alexandra L. F Blakemore, Ken K. Ong, Vincent W.V Jaddoe, Struan F.A Grant, Sylvain Sebert, Mark L. McCarthy, Marjo-Riitta Jarvelin (2019)GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI, In: Science Advances5(9) American Association for the Advancement of Science

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.