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1. Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author

Martina Müller-Nurasyid, Jerome I. Rotter, David M. Evans, John P. Kemp, Emelia J. Benjamin, Graciela E. Delgado, Vilmundur Gudnason, Ann Hammarstedt, Panos Deloukas, Aroon D. Hingorani, Riccardo E. Marioni, David Stacey, Jenny van Dongen, Eric Boerwinkle, Joachim Heinrich, Yongmei Liu, S. Goya Wannamethee, Delilah Zabaneh, Braxton D. Mitchell, Marie Standl, Jackie F. Price, Maria G. Stathopoulou, Yoav Ben-Shlomo, Joris Deelen, Eero Kajantie, Mohammadreza Abdollahi, Christie M. Ballantyne, Johan G. Eriksson, Ilkka Seppälä, Elnaz Naderi, Barbara J. Jefferis, Richard W Morris, Nicholas J. Timpson, George Dedoussis, Sirpa Jalkanen, Mika Kivimäki, Perminder S. Sachdev, Diana van Heemst, Melanie Waldenberger, Gaurav Singhal, Elisabeth Thiering, Olli T. Raitakari, Anders Hamsten, Zoltán Kutalik, L. Bain, Eco J. C. de Geus, Tarunveer S. Ahluwalia, Yuri Milaneschi, Hubert Scharnagl, Juan P. Casas, Georg Homuth, Claes Ohlsson, Abbas Dehghan, Nicola J. Armstrong, Behrooz Z. Alizadeh, Terho Lehtimäki, Steve E. Humphries, Naveed Sattar, Bram P. Prins, Peter Rossing, Sophie Visvikis-Siest, Joana A. Revez, Ilja M. Nolte, Stella Trompet, Harold Snieder, Marian Beekman, Diana Marek, Beate St Pourcain, Thorkild I. A. Sørensen, Silvia Naitza, Karen A. Mather, Uwe Völker, Eline Slagboom, Tina Shah, Magdalene C. Jawahar, Jens Baumert, Alexander Teumer, Dorret I. Boomsma, Marcus E. Kleber, Peter Vollenweider, Wolfgang Koenig, Brenda W.J.H. Penninx, Kenneth Rice, Ian J. Deary, Pedro Marques-Vidal, Donna K. Arnett, Eleonora Porcu, Jouke-Jan Hottenga, Maria Sabater-Lleal, Bruce M. Psaty, Matthias Nauck, Dan Mellström, Joel Eriksson, Bernhard T. Baune, Debbie A Lawlor, Catherine Toben, Peter H. Whincup, Toshiko Tanaka, Stavroula Kanoni, Katri Räikkönen, Gonneke Willemsen, Bengt Sennblad, Julian N. Trollor, Yalda Jamshidi, Sarah E. Harris, Jari Lahti, Joshua C. Bis, Peter Durda, Yen Pei C. Chang, Jorgen Engmann, Tom R. Gaunt, Stella Aslibekyan, Anbupalam Thalamuthu, Mary F. Feitosa, Angela Silveira, Tine Jess, Stela McLachlan, J. Wouter Jukema, Chen Lu, Simon P. Mooijaart, Tim D. Spector, Harald Grallert, Winfried März, Alexandros M. Petrelis, Manuel A. R. Ferreira, Meena Kumari, Stochastics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, APH - Methodology, CHARGE Inflammation Working Group, Epidemiology, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Steno Diabetes Center, University of Copenhagen = Københavns Universitet (KU), University of Groningen [Groningen], Murdoch University, University of Alabama at Birmingham [ Birmingham] (UAB), QIMR Berghofer Medical Research Institute, University College of London [London] (UCL), Helmholtz-Zentrum München (HZM), Leiden University Medical Center (LUMC), University of Bristol [Bristol], University of Washington [Seattle], University of Maryland School of Medicine, University of Maryland System, Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], University of Heidelberg, Medical Faculty, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Sahlgrenska Academy at University of Gothenburg [Göteborg], National Institute for Health and Welfare [Helsinki], University of Helsinki, William Harvey Research Institute, Barts and the London Medical School, University of Queensland [Brisbane], School of Public Health [Boston], Boston University [Boston] (BU), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, University of Edinburgh, Amsterdam UMC, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), Karolinska Institutet [Stockholm], University of Tampere [Finland], Adelaide Medical School [Australia], University of Adelaide, Universität Greifswald - University of Greifswald, University of New South Wales [Sydney] (UNSW), Prince of Wales Hospital, Ludwig-Maximilians-Universität München (LMU), Baylor College of Medicine (BCM), Baylor University, Boston University School of Medicine (BUSM), VA Boston Healthcare System, Harokopio University of Athens, Max planck Institute for Biology of Ageing [Cologne], Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, University of Turku, St George's, University of London, Statens Serum Institut [Copenhagen], Medical Faculty [Mannheim], Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Johannes Gutenberg - Universität Mainz (JGU), Vrije Universiteit Medical Centre (VUMC), British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Medical University Graz, Uppsala Universitet [Uppsala], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Kentucky, Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of Maryland [Baltimore], Queen Mary University of London (QMUL), University of Iceland [Reykjavik], Ludwig Maximilian University [Munich] (LMU), Melbourne School of Population and Global Health [Melbourne], University of Melbourne, Deutsches Herzzentrum München (DHM), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Ulm (UUlm), University of Essex, Greifswald University Hospital, Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), King‘s College London, University of Cambridge [UK] (CAM), Harbor UCLA Medical Center [Torrance, Ca.], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Human Genome Sequencing Center [Houston] (HGSC), Baylor University-Baylor University, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, HUS Children and Adolescents, Lastentautien yksikkö, Children's Hospital, Clinicum, Department of Bacteriology and Immunology, Department of Public Health, Department of Psychology and Logopedics, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Doctoral Programme in Human Behaviour, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
AcademicSubjects/SCI01140, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, DISEASE, Pathogenesis, Cohort Studies, 0302 clinical medicine, cytokine, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Association Studies Article, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genetics, 0303 health sciences, ARCHITECTURE, CHRONIC INFLAMMATION, 1184 Genetics, developmental biology, physiology, General Medicine, RECEPTOR IL-6R GENE, C-REACTIVE PROTEIN, hla-drb1 gene, 3. Good health, Medical genetics, Medical Genetics, chromosomes, medicine.medical_specialty, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, anti-inflammatory agents, White People, 03 medical and health sciences, medicine, Humans, Genetic Predisposition to Disease, Interleukin 6, Molecular Biology, Medicinsk genetik, 030304 developmental biology, PRODUCE IL-6, Interleukin-6, Chromosome, Receptors, Interleukin-6, RHEUMATOID-ARTHRITIS, Interleukin 1 Receptor Antagonist Protein, Gene Expression Regulation, Genetic Loci, CELLS, biology.protein, 1182 Biochemistry, cell and molecular biology, Human genome, 3111 Biomedicine, Genome-Wide Association Study, HLA-DRB1 Chains, Interleukin-1
Abstract

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Published
2021

2. Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Author

Dan Rujescu, Vidar M. Steen, Eva Krapohl, Aarno Palotie, Elisabeth Widen, Ingrid Melle, Patrick Sullivan, Katrina L. Grasby, Stephan Ripke, Anke R. Hammerschlag, Christiaan de Leeuw, Panos Bitsios, Nikos C. Stefanis, Tonya White, Gail Davies, Ahmad R. Hariri, Philip R. Jansen, Peter B. Barr, John M. Starr, Max Lam, Ian J. Deary, Sara Hägg, Dimitrios Avramopoulos, Bettina Konte, Anil K. Malhotra, Delilah Zabaneh, Kjetil Sundet, Tinca J. C. Polderman, Ornit Chiba-Falek, Jakob Kaminski, Danielle M. Dick, Andrea Christoforou, Jin Yu, Gunter Schumann, Matthew A. Scult, Anna C. Need, Jens Hjerling-Leffler, Gonçalo R. Abecasis, Kenneth S. Kendler, Todd Lencz, Dwight Dickinson, Bradley T. Webb, Elizabeth T. Cirulli, Stephanie Le Hellard, Gerome Breen, Astri J. Lundervold, Hannah Young, Erin Burke Quinlan, William Ollier, Nikolaos Smyrnis, Emily Drabant Conley, Danielle Posthuma, Sten Linnarsson, Aristotle N. Voineskos, Edythe D. London, Pamela DeRosse, Russell A. Poldrack, Jonathan R. I. Coleman, Jeanne E. Savage, Sarah E. Medland, Ana B. Muñoz-Manchado, Richard E. Straub, Robert Plomin, Ida K. Karlsson, Nathan G. Skene, Dan E. Arking, Birgit Debrabant, Joey W. Trampush, Matthew C. Keller, Mats Nagel, Gary Donohoe, Chandra A. Reynolds, Panos Roussos, Lene Christiansen, Ivar Reinvang, Ole A. Andreassen, Antony Payton, Robert Karlsson, Margaret J. Wright, Deborah C. Koltai, Jari Lahti, Andreas Heinz, Tyrone D. Cannon, Eliza Congdon, Olav B. Smeland, Stella G. Giakoumaki, Marianne Nygaard, Julien Bryois, M. Arfan Ikram, Nancy L. Pedersen, Katri Räikkönen, Daniel R. Weinberger, Neil Pendleton, Swapnil Awasthi, Sven Stringer, Nelson A. Freimer, Aiden Corvin, Kyoko Watanabe, David C. Glahn, Henning Tiemeier, Grant W. Montgomery, Narelle K. Hansell, Robert M. Bilder, Katherine E. Burdick, Srdjan Djurovic, David C. Liewald, Sophie van der Sluis, Thomas Espeseth, Scott I. Vrieze, Fred W. Sabb, Nicholas G. Martin, Michael Gill, Emma Knowles, Derek W. Morris, Alex Hatzimanolis, Ina Giegling, Johan G. Eriksson, Child and Adolescent Psychiatry / Psychology, Epidemiology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Biological Psychology, Functional Genomics, Research Programs Unit, Diabetes and Obesity Research Program, Department of General Practice and Primary Health Care, Johan Eriksson / Principal Investigator, Clinicum, University of Helsinki, Medicum, Helsinki Collegium for Advanced Studies, Department of Psychology and Logopedics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Elisabeth Ingrid Maria Widen / Principal Investigator, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, VU University medical center, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Nonsynonymous substitution, Male, GENERAL COGNITIVE FUNCTION, Intelligence, LOCI, Genome-wide association study, ANNOTATION, 0302 clinical medicine, GWAS, 11 Medical and Health Sciences, Genetics & Heredity, RISK, HERITABILITY, Brain, Mendelian Randomization Analysis, Middle Aged, 3. Good health, Schizophrenia, Genome-Wide Association Study/methods, Female, Life Sciences & Biomedicine, TRAITS, Adolescent, Quantitative Trait Loci, Computational biology, Biology, Quantitative trait locus, Brain/physiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetic association, EDUCATIONAL-ATTAINMENT, Science & Technology, TEST BATTERIES, CONSORTIUM, Intelligence/genetics, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Expression quantitative trait loci, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Published
2018

3. Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Author

Gerome Breen, Suzanne Sniekers, Neil Pendleton, Robert Plomin, Antony Payton, Magnus Johannesson, Anke R. Hammerschlag, Sven Stringer, Philipp Koellinger, Matt McGue, David Cesarini, Najaf Amin, Christopher F. Chabris, Delilah Zabaneh, Cornelia M. van Duijn, Cornelius A. Rietveld, Aysu Okbay, Jonathan R. I. Coleman, Michael B. Miller, Danielle Posthuma, Eva Krapohl, Erdogan Taskesen, William G. Iacono, Kyoko Watanabe, Philip R. Jansen, Patrik K. E. Magnusson, William E R Ollier, James J. Lee, Henning Tiemeier, M. Arfan Ikram, Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, Child and Adolescent Psychiatry / Psychology, Applied Economics, Epidemiology, Psychiatry, Mathematics, Complex Trait Genetics, Tinbergen Institute, Graduate School, and Human Genetics

Subjects
0301 basic medicine, Adult, Male, Linkage disequilibrium, Adolescent, European Continental Ancestry Group, Intelligence, Single-nucleotide polymorphism, Genome-wide association study, Nerve Tissue Proteins, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Article, White People, Linkage Disequilibrium, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetics, Journal Article, Brain/metabolism, Nerve Tissue Proteins/genetics, Humans, Polymorphism, Child, Preschool, Gene, Aged, Human intelligence, Research, Intelligence/genetics, Brain, Infant, Single Nucleotide, Heritability, Middle Aged, Genetic architecture, 030104 developmental biology, Child, Preschool, Female, 030217 neurology & neurosurgery, White People/genetics, Genome-Wide Association Study, Meta-Analysis
Abstract

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta- A nalysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10-6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10-6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10-29). These findings provide new insight into the genetic architecture of intelligence.

Published
2017

4. HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics

Author

Lea Trela-Larsen, Yi Zheng, Jie Zheng, Meena Kumari, Aroon D. Hingorani, Richard W Morris, Claudia Giambartolomei, A. Mesut Erzurumluoglu, Delilah Zabaneh, Denis Baird, Jon White, Charles Laurin, David M. Evans, Ian N. M. Day, Tom R. Gaunt, Santiago Rodriguez, and Juan P. Casas

Subjects
0301 basic medicine, Statistics and Probability, medicine.medical_specialty, Genotype, Computer science, Iterative method, Genome-wide association study, 030105 genetics & heredity, computer.software_genre, Biochemistry, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Unit (housing), 03 medical and health sciences, Quantitative Trait, Heritable, Gene Frequency, Epidemiology, medicine, Humans, Molecular Biology, Haplotype, Chromosome Mapping, Data science, Summary statistics, Computer Science Applications, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, Haplotypes, Sample Size, Data mining, computer, Software, Genome-Wide Association Study
Abstract

Motivation Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients (r2) of the variants. However, haplotypes rather than pairwise r2, are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. Results Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N Availability and Implementation The HAPRAP package and documentation are available at http://apps.biocompute.org.uk/haprap/ Supplementary information Supplementary data are available at Bioinformatics online.

Published
2016

5. Cystatin C and Cardiovascular Disease

Author

Heribert Schunkert, Wolfgang Koenig, Jessica van Setten, Meena Kumari, Johan Ärnlöv, J. Wouter Jukema, Vinicius Tragante, Alanna C. Morrison, Bradford B. Worrall, Brendan J. Keating, Alexander Teumer, Vilmantas Giedraitis, Tom Wilsgaard, Nilesh J. Samani, Barbara Thorand, Patricia B. Munroe, Rainer Malik, Melanie Waldenberger, Christopher P. Nelson, Sebastian E. Baumeister, Aroon D. Hingorani, Stéphanie Debette, Tove Fall, Patrik K. E. Magnusson, Nora Franceschini, Anders Larsson, Andrew P. Morris, Folkert W. Asselbergs, Maryam Kavousi, Oscar H. Franco, Jeanette Erdmann, Jonathan Marchini, Mika Kivimäki, Ivana Išgum, Fotios Drenos, N. Charlotte Onland-Moret, Bjørn Odvar Eriksen, Aicha Soumare, Christopher J. O'Donnell, Ingrid Toft, Paul I.W. de Bakker, Johannes Arpegård, Jacqueline de Graaf, Abbas Dehghan, Delilah Zabaneh, Michael V. Holmes, Yvonne T. van der Schouw, Alexander P. Reiner, André G. Uitterlinden, Christa Meisinger, Janine F. Felix, Erik Ingelsson, Lars Lind, Martin Dichgans, Marcus Dörr, Albert Hofman, Sanaz Sedaghat, Lambertus A. Kiemeney, Joshua C. Bis, Jens Baumert, Tessel E. Galesloot, Hester M. den Ruijter, Gerard Pasterkamp, Annette Peters, Naveed Sattar, Nancy L. Pedersen, Pim van der Harst, Stella Trompet, Per Svensson, Riyaz S. Patel, Philippe Amouyel, and Sander W. van der Laan

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Population, Renal function, 030204 cardiovascular system & hematology, urologic and male genital diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Mendelian randomization, medicine, education, education.field_of_study, biology, business.industry, Confounding, Mendelian Randomization Analysis, 3. Good health, Minor allele frequency, 030104 developmental biology, Cystatin C, biology.protein, Cystatin, Cardiology and Cardiovascular Medicine, business
Abstract

BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license.

Published
2016

6. A genome-wide association study for extremely high intelligence

Author

Gerome Breen, Robert Plomin, H M Wu, Eva Krapohl, Delilah Zabaneh, Helena Gaspar, Martha Putallaz, Charles Curtis, Hamel Patel, Sang Hyuck Lee, Stephen Newhouse, David Lubinski, Michael A. Simpson, Zabaneh, D, Krapohl, E, Gaspar, HA, Curtis, C, Lee, Sang Hong, Patel, H, Newhouse, S, Wu, HM, Simpson, MA, Putallaz, M, Lubinski, D, Plomin, R, and Breen, G

Subjects
Adult, Male, 0301 basic medicine, Multifactorial Inheritance, Adolescent, Intelligence, Population, ADAM12 Protein, Locus (genetics), Genome-wide association study, Quantitative trait locus, high intelligence, Polymorphism, Single Nucleotide, genetic study, 03 medical and health sciences, Cellular and Molecular Neuroscience, Quantitative Trait, Heritable, genome-wide association (GWA), Humans, Longitudinal Studies, education, Molecular Biology, Genetics, education.field_of_study, Heritability, Explained variation, Psychiatry and Mental health, Phenotype, 030104 developmental biology, Sample size determination, Case-Control Studies, educational attainment, Trait, Original Article, Female, Psychology, Genome-Wide Association Study, Clinical psychology
Abstract

We used a case-control genome-wide association (GWA) design with cases consisting of 1238 individuals from the top 0.0003 (∼170 mean IQ) of the population distribution of intelligence and 8172 unselected population-based controls. The single-nucleotide polymorphism heritability for the extreme IQ trait was 0.33 (0.02), which is the highest so far for a cognitive phenotype, and significant genome-wide genetic correlations of 0.78 were observed with educational attainment and 0.86 with population IQ. Three variants in locus ADAM12 achieved genome-wide significance, although they did not replicate with published GWA analyses of normal-range IQ or educational attainment. A genome-wide polygenic score constructed from the GWA results accounted for 1.6% of the variance of intelligence in the normal range in an unselected sample of 3414 individuals, which is comparable to the variance explained by GWA studies of intelligence with substantially larger sample sizes. The gene family plexins, members of which are mutated in several monogenic neurodevelopmental disorders, was significantly enriched for associations with high IQ. This study shows the utility of extreme trait selection for genetic study of intelligence and suggests that extremely high intelligence is continuous genetically with normal-range intelligence in the population. usc Refereed/Peer-reviewed

Published
2018

7. Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations

Author

Meena Kumari, John R. B. Perry, Jian'an Luan, Robert A. Scott, Delilah Zabaneh, Michaela Benzeval, Eleftheria Zeggini, Claudia Langenberg, Nicholas J. Wareham, Karoline Kuchenbaecker, Melissa C. Smart, Bram P. Prins, Ghazaleh Fatemifar, Yanchun Bao, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Perry, John [0000-0001-6483-3771], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Genetic Markers, Longitudinal study, Health Status, lcsh:Medicine, Genome-wide association study, Article, 03 medical and health sciences, Liver disease, medicine, Longitudinal Studies, 1000 Genomes Project, lcsh:Science, Genetics, Family Health, Family Characteristics, Multidisciplinary, biology, Haplotype, lcsh:R, medicine.disease, Genetic architecture, United Kingdom, 3. Good health, 030104 developmental biology, Reproductive Health, Alanine transaminase, biology.protein, Biomarker (medicine), lcsh:Q, Biomarkers, Genome-Wide Association Study
Abstract

Serum biomarker levels are associated with the risk of complex diseases. Here, we aimed to gain insights into the genetic architecture of biomarker traits which can reflect health status. We performed genome-wide association analyses for twenty serum biomarkers involved in organ function and reproductive health. 9,961 individuals from the UK Household Longitudinal Study were genotyped using the Illumina HumanCoreExome array and variants imputed to the 1000 Genomes Project and UK10K haplotypes. We establish a polygenic heritability for all biomarkers, confirm associations of fifty-four established loci, and identify five novel, replicating associations at genome-wide significance. A low-frequency variant, rs28929474, (beta = 0.04, P = 2 × 10−10) was associated with levels of alanine transaminase, an indicator of liver damage. The variant is located in the gene encoding serine protease inhibitor, low levels of which are associated with alpha-1 antitrypsin deficiency which leads to liver disease. We identified novel associations (rs78900934, beta = 0.05, P = 6 × 10−12; rs2911280, beta = 0.09, P = 6 × 10−10) for dihydroepiandrosterone sulphate, a precursor to major sex-hormones, and for glycated haemoglobin (rs12819124, beta = −0.03, P = 4 × 10−9; rs761772, beta = 0.05, P = 5 × 10−9). rs12819124 is nominally associated with risk of type 2 diabetes. Our study offers insights into the genetic architecture of well-known and less well-studied biomarkers.

Published
2017

8. Erratum: Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Author

Suzanne Sniekers, Sven Stringer, Kyoko Watanabe, Philip R Jansen, Jonathan R I Coleman, Eva Krapohl, Erdogan Taskesen, Anke R Hammerschlag, Aysu Okbay, Delilah Zabaneh, Najaf Amin, Gerome Breen, David Cesarini, Christopher F Chabris, William G Iacono, M Arfan Ikram, Magnus Johannesson, Philipp Koellinger, James J Lee, Patrik K E Magnusson, Matt McGue, Mike B Miller, William E R Ollier, Antony Payton, Neil Pendleton, Robert Plomin, Cornelius A Rietveld, Henning Tiemeier, Cornelia M van Duijn, Danielle Posthuma, Clinical genetics, NCA - Brain mechanisms in health and disease, VU University medical center, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Psychiatry

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Genetics, Journal Article, 030217 neurology & neurosurgery, 030304 developmental biology
Published
2017

9. GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence

Author

Lene Christiansen, Robert M. Bilder, Katherine E. Burdick, Tinca J. C. Polderman, Ana B. Muñoz-Manchado, Gary Donohoe, Matthew C. Keller, Stephan Ripke, Anil K. Malhotra, Delilah Zabaneh, Andrea Christoforou, Matthew A. Scult, Nikolaos Smyrnis, Scott I. Vrieze, Fred W. Sabb, Stella G. Giakoumaki, Nathan G. Skene, Ole A. Andreassen, Nicholas G. Martin, Jari Lahti, Anna C. Need, Philip R. Jansen, Todd Lencz, Emma Knowles, Peter B. Barr, Pamela DeRosse, Russell A. Poldrack, Henning Tiemeier, Sten Linnarsson, Hannah Young, Emily Drabant Conley, Dan E. Arking, Jin Yu, Grant W. Montgomery, Danielle Posthuma, Dwight Dickinson, Elizabeth T. Cirulli, Gerome Breen, Gunter Schumann, Michael Gill, Erin Burke Quinlan, Robert Plomin, Kyoko Watanabe, Joey W. Trampush, John M. Starr, Katri Räikkönen, Narelle K. Hansell, Eliza Congdon, Olav B. Smeland, Jens Hjerling-Leffler, Richard E. Straub, Aiden Corvin, Chandra A. Reynolds, Astri J. Lundervold, Bradley T. Webb, Gonçalo R. Abecasis, Jonathan R. I. Coleman, Srdjan Djurovic, Margaret J. Wright, Kjetil Sundet, Ivar Reinvang, Robert Karlsson, Deborah C. Koltai, Ina Giegling, Alex Hatzimanolis, David C. Liewald, William Ollier, Sophie van der Sluis, Edythe D. London, Tyrone D. Cannon, Thomas Espeseth, M. Arfan Ikram, Ian J. Deary, Christiaan de Leeuw, Daniel R. Weinberger, Neil Pendleton, Ornit Chiba-Falek, Jakob Kaminski, Danielle M. Dick, Panos Bitsios, Nikos C. Stefanis, Tonya White, Bettina Konte, Ida K. Karlsson, Mats Nagel, Derek W. Morris, Anke R. Hammerschlag, Swapnil Awasthi, Antony Payton, Julien Bryois, Nelson A. Freimer, Nancy L. Pedersen, Panos Roussos, Andreas Heinz, Johan G. Eriksson, Marianne Nygaard, Birgit Debrabant, Aarno Palotie, Elisabeth Widen, Aristotle N. Voineskos, Patrick Sullivan, Ingrid Melle, Dan Rujescu, Vidar M. Steen, Eva Krapohl, Katrina L. Grasby, Max Lam, Stephanie Le Hellard, Kenneth S. Kendler, Jeanne E. Savage, Sarah E. Medland, Sven Stringer, David C. Glahn, Gail Davies, Ahmad R. Hariri, Sara Hägg, and Dimitrios Avramopoulos

Subjects
Genetics, Nonsynonymous substitution, 0303 health sciences, Genome-wide association study, Biology, 03 medical and health sciences, 0302 clinical medicine, Pleiotropy, Mendelian randomization, Expression quantitative trait loci, Neuron differentiation, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to intelligence3–7, but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimer’s dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.

Published
2017
Full Text
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10. Erratum

Author

Deepali Jaju, Melanie Neijts, Gabrielle Boucher, Arpi Minassian, James D. Stewart, Andreas Voss, Pim van der Harst, Duanping Liao, Joshua C. Bis, Kari E. North, Matteo Barcella, Michel G. Nivard, Jitender Kumar, Andrew Wong, Dewleen G. Baker, G. Ehret, Sulayma Albarwani, Kathleen F. Kerr, Quenna Wong, Ville Huikari, Alexander Kluttig, Andrew P. Morris, Eco J. C. de Geus, Albertine J. Oldehinkel, Ann-Christine Syvänen, Martina Mueller-Nurasyid, Yong Li, Marcel den Hoed, Henning Tiemeier, Henriette E. Meyer zu Schwabedissen, Dorret I. Boomsma, Joop D. Lefrandt, Mohammad Hadi Zafarmand, Victoria B. Risbrough, Halina Greiser, Bruce M. Psaty, Oscar H. Franco, Niek Verweij, Cees A. Swenne, Antti M. Kiviniemi, Konstantin Strauch, Markus Juonala, Zhu Ming Zhang, Nicholas L. Smith, Olli T. Raitakari, Daiane Hemerich, Daniel T. O'Connor, Christopher J. O'Donnell, Riad Bayoumi, Peter Friberg, Alvaro Alonso, Julian F. Thayer, Caroline M. Nievergelt, Delilah Zabaneh, Steven A. Lubitz, Tomas Axelsson, Terho Lehtimäki, Daniele Cusi, Eric A. Whitsel, Arie M. van Roon, Kjell Nikus, Bruno H. Stricker, Bouwe P. Krijthe, Stefan Kääb, Lars Lind, Abdel Abdellaoui, Timothy A. Thornton, Anubha Mahajan, Johan Sundström, Nona Sotoodehnia, Charles Kooperberg, Moritz F. Sinner, Leo-Pekka Lyytikäinen, Xavier Jouven, Tanja G. M. Vrijkotte, Sander W. van der Laan, Tatiana Kuznetsova, Patrick T. Ellinor, Alexander P. Reiner, Ilja M. Nolte, Marian C. Limacher, Paul I.W. de Bakker, Ahmad Vaez, Albert Hofman, Meena Kumari, Folkert W. Asselbergs, Juhani Junttila, Bram Dierckx, Marjo-Riitta Järvelin, Ingrid E. Christophersen, Annie Britton, Cathy C. Laurie, Phyllis K. Stein, Katarzyna Stolarz-Skrzypek, Juha Auvinen, Alexander Teumer, Vilmantas Giedraitis, Foram N. Ashar, Jenny van Dongen, David S. Siscovick, Markku Eskola, Jussi Hernesniemi, Janine F. Felix, M. Loretto Munoz, Jessica van Setten, Yun Li, Bianca J. J. M. Brundel, Christine M. Albert, Annette Peters, Jerome I. Rotter, Nina Hutri-Kähönen, Mark A. Geyer, Lesley E. Tinker, Vinicius Tragante, Susan R. Heckbert, Alan B. Zonderman, John D. Rioux, Kent D. Taylor, Shih-Jen Hwang, Johan Ormel, Mike A. Nalls, Erik Ingelsson, Kirk C. Wilhelmsen, John S. Floras, Diana Kuh, Elsayed Z. Soliman, Henry J. Lin, Brenda W.J.H. Penninx, Mika Kivimäki, Maaike G. J. Gademan, Jouke-Jan Hottenga, Mika Kähönen, Gerjan Navis, Siegfried Perz, Tamar Sofer, Catharina A. Hartman, Barbara McKnight, Jan A. Kors, Rick Jansen, Melanie Waldenberger, Nina Mononen, Heikki V. Huikuri, Azmeraw T. Amare, Mohammad L. Hassan, Jan A. Staessen, Adam X. Maihofer, Erika Salvi, Rob J. Bieringa, Benedikt von der Heyde, Andrea Dietrich, Peter J. van der Most, Philippe Goyette, Harriëtte Riese, Michele K. Evans, Stephanie M. Gogarten, Jean-Claude Tardif, Harold Snieder, Adrienne M. Stilp, Christy L. Avery, Johannes H. Smit, Gonneke Willemsen, Yuri Milaneschi, André G. Uitterlinden, Cecilia M. Lindgren, VU University medical center, APH - Mental Health, Psychiatry, Physiology, ACS - Heart failure & arrhythmias, APH - Methodology, and APH - Digital Health

Subjects
0301 basic medicine, Genetics, Multidisciplinary, Science, General Physics and Astronomy, General Chemistry, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Disease risk, Heart rate variability, 030217 neurology & neurosurgery
Abstract

Nature Communications 8: Article number: 15805 (2017); Published: 14 June 2017; Updated: 2 August 2017 In Supplementary Fig. 10 of this Article, images for panels a and b were inadvertently omitted. The correct version of Supplementary Fig. 10 is provided as Supplementary Information associated withthis Erratum.

Published
2017

11. Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Author

Gerjan Navis, Moritz F. Sinner, Kathleen F. Kerr, Heikki V. Huikuri, Daniele Cusi, Oscar H. Franco, Marian C. Limacher, Charles Kooperberg, Gabrielle Boucher, Riad Bayoumi, Juhani Junttila, Ann-Christine Syvänen, Andrew P. Morris, Anubha Mahajan, Andreas Voss, Paul I.W. de Bakker, Patrick T. Ellinor, Phyllis K. Stein, Janine F. Felix, Mark A. Geyer, Mike A. Nalls, Erik Ingelsson, Vinicius Tragante, Joshua C. Bis, Kari E. North, Jean-Claude Tardif, Harold Snieder, Azmeraw T. Amare, Katarzyna Stolarz-Skrzypek, Markku Eskola, Ilja M. Nolte, Tanja G. M. Vrijkotte, Elsayed Z. Soliman, Deepali Jaju, Melanie Neijts, Adrienne M. Stilp, Mika Kähönen, Henry J. Lin, Jessica van Setten, Meena Kumari, Halina Greiser, John S. Floras, Henriette E. Meyer zu Schwabedissen, Mohammad Hadi Zafarmand, Dewleen G. Baker, Rick Jansen, Cathy C. Laurie, Matteo Barcella, Christy L. Avery, Stefan Kääb, Michel G. Nivard, Jitender Kumar, Lars Lind, Alexander Teumer, Johan Sundström, Kirk C. Wilhelmsen, Barbara McKnight, Vilmantas Giedraitis, Johannes H. Smit, Gonneke Willemsen, Nona Sotoodehnia, Michele K. Evans, Christine M. Albert, Kent D. Taylor, Marcel den Hoed, James D. Stewart, Peter Friberg, Alvaro Alonso, Susan R. Heckbert, Kjell Nikus, Siegfried Perz, André G. Uitterlinden, Bruce M. Psaty, Antti M. Kiviniemi, G. Ehret, Jouke-Jan Hottenga, Sulayma Albarwani, Bouwe P. Krijthe, Timothy A. Thornton, Caroline M. Nievergelt, Delilah Zabaneh, Zhu Ming Zhang, Annie Britton, Ingrid E. Christophersen, Adam X. Maihofer, Juha Auvinen, David S. Siscovick, Arie M. van Roon, Xavier Jouven, Stephanie M. Gogarten, M. Loretto Munoz, Erika Salvi, Folkert W. Asselbergs, Bram Dierckx, Marjo-Riitta Järvelin, Cecilia M. Lindgren, Yun Li, Quenna Wong, Alan B. Zonderman, Yuri Milaneschi, John D. Rioux, Brenda W.J.H. Penninx, Philippe Goyette, Niek Verweij, Harriëtte Riese, Bruno H. Stricker, Markus Juonala, Rob J. Bieringa, Arpi Minassian, Jenny van Dongen, Abdel Abdellaoui, Foram N. Ashar, Jan A. Kors, Albertine J. Oldehinkel, Jussi Hernesniemi, Sander W. van der Laan, Ahmad Vaez, Nina Hutri-Kähönen, Annette Peters, Lesley E. Tinker, Albert Hofman, Dorret I. Boomsma, Victoria B. Risbrough, Tamar Sofer, Pim van der Harst, Konstantin Strauch, Steven A. Lubitz, Catharina A. Hartman, Jerome I. Rotter, Shih-Jen Hwang, Duanping Liao, Mika Kivimäki, Mohammad L. Hassan, Andrew Wong, Peter J. van der Most, Alexander Kluttig, Nina Mononen, Eco J. C. de Geus, Henning Tiemeier, Benedikt von der Heyde, Martina Müller-Nurasyid, Joop D. Lefrandt, Andrea Dietrich, Nicholas L. Smith, Terho Lehtimäki, Bianca J. J. M. Brundel, Jan A. Staessen, Cees A. Swenne, Julian F. Thayer, Daniel T. O'Connor, Christopher J. O'Donnell, Eric A. Whitsel, Tatiana Kuznetsova, Alexander P. Reiner, Johan Ormel, Ville Huikari, Yong Li, Tomas Axelsson, Olli T. Raitakari, Daiane Hemerich, Leo-Pekka Lyytikäinen, Maaike G. J. Gademan, Melanie Waldenberger, Diana Kuh, Ehret, Georg Benedikt, APH - Personalized Medicine, APH - Global Health, Other Research, ACS - Amsterdam Cardiovascular Sciences, Public and occupational health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, ARD - Amsterdam Reproduction and Development, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Physiology, ACS - Heart failure & arrhythmias, APH - Digital Health, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Vascular Ageing Programme (VAP), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Value, Affordability and Sustainability (VALUE), Biological Psychology, Praxis, Environmental Geography (former), Child and Adolescent Psychiatry / Psychology, Rheumatology, Epidemiology, Medical Informatics, and Internal Medicine

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Medicin och hälsovetenskap, Potassium Channels, Chemistry(all), Muscle Proteins, General Physics and Astronomy, Genome-wide association study, Blood Pressure, PEDIGREES, Bioinformatics, Biochemistry, Genome-wide association studies, Medical and Health Sciences, Cohort Studies, Heart Rate, Risk Factors, RGS Proteins/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, RECORDINGS, Heart rate variability, Vagal tone, European Continental Ancestry Group/genetics, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics, ddc:616, Muscle Proteins/genetics, Multidisciplinary, digestive, oral, and skin physiology, Single Nucleotide, Multidisciplinary Sciences, Science & Technology - Other Topics, Heart Diseases/genetics/physiopathology, Erratum, circulatory and respiratory physiology, Heart Diseases, Science, Quantitative Trait Loci, RESPIRATORY SINUS ARRHYTHMIA, Quantitative trait locus, Biology, Physics and Astronomy(all), Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Article, PARASYMPATHETIC REGULATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Heart rate, Journal Article, Humans, Genetic Predisposition to Disease, COHORT, Polymorphism, GENOME-WIDE ASSOCIATION, METAANALYSIS, Genetic association, MODULATOR, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), MORTALITY, Cardiovascular genetics, General Chemistry, Membrane hyperpolarization, ta3121, 030104 developmental biology, Expression quantitative trait loci, ATRIAL-FIBRILLATION, Potassium Channels/genetics, RGS Proteins, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74, Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.

Published
2017

12. Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis

Author

Helen R. Warren, Bradford B. Worrall, Jorgen Engmann, Tom R. Gaunt, David Prieto-Merino, Usha Menon, Dennis O. Mook-Kanamori, Aroon D. Hingorani, Meena Kumari, Mika Kivimäki, Ang Zhou, Michael V. Holmes, Aleksandra Gentry-Maharaj, Barbara J. Jefferis, Delilah Zabaneh, Mark J. Caulfield, Reecha Sofat, Renée de Mutsert, Chris Power, Yoav Ben-Shlomo, J. Wouter Jukema, Tom Palmer, Richard W Morris, Tina Shah, Juan P. Casas, Diana Kuh, Max Moldovan, Debbie A Lawlor, Jacqueline F. Price, Andrew Wong, Raymond Noordam, Caroline Dale, Steve E. Humphries, Naveed Sattar, Stella Trompet, Jon White, Stela McLachlan, George Davey Smith, Frank Dudbridge, Patricia B. Munroe, Andy Ryan, Elina Hyppönen, Ghazaleh Fatemifar, Dale, Caroline E, Fatemifar, Ghazaleh, Palmer, Tom M, White, Jon, Hyppönen, Elina, Zhou, Ang, and Casas, Juan P

Subjects
0301 basic medicine, medicine.medical_specialty, Mendelian randomization analysis, body fat distribution, body mass index, Coronary Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Waist–hip ratio, Physiology (medical), Internal medicine, Diabetes mellitus, Mendelian randomization, medicine, Body Fat Distribution, Humans, Longitudinal Studies, Prospective Studies, Stroke, Adiposity, adiposity, business.industry, Type 2 Diabetes Mellitus, Odds ratio, Mendelian Randomization Analysis, medicine.disease, stroke, Observational Studies as Topic, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Cardiology, waist-hip ratio, Cardiology and Cardiovascular Medicine, business, Body mass index, coronary artery disease, Bristol Population Health Science Institute
Abstract

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease. Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits. Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28–1.71), similar to findings for BMI (1 SD≈4.6 kg/m 2 ; OR for CHD, 1.36; 95% CI, 1.22–1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03–1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38–2.42) and OR, 1.98 (95% CI, 1.41–2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%–77% per 1 SD). Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.

Published
2017

13. Fine mapping genetic associations between the HLA region and extremely high intelligence

Author

David Lubinski, Delilah Zabaneh, William G. Iacono, Gerome Breen, Michael A. Simpson, Michael B. Miller, Robert Plomin, Martha Putallaz, Matt McGue, and Eva Krapohl

Subjects
0301 basic medicine, Genetics, Male, Multifactorial Inheritance, Multidisciplinary, Genotype, Intelligence, Chromosome Mapping, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 030104 developmental biology, Missing heritability problem, HLA Antigens, Case-Control Studies, Genetic variation, SNP, Humans, Female
Abstract

General cognitive ability (intelligence) is one of the most heritable behavioural traits and most predictive of socially important outcomes and health. We hypothesized that some of the missing heritability of IQ might lie hidden in the human leukocyte antigen (HLA) region, which plays a critical role in many diseases and traits but is not well tagged in conventional GWAS. Using a uniquely powered design, we investigated whether fine-mapping of the HLA region could narrow the missing heritability gap. Our case-control design included 1,393 cases with extremely high intelligence scores (top 0.0003 of the population equivalent to IQ > 147) and 3,253 unselected population controls. We imputed variants in 200 genes across the HLA region, one SNP (rs444921) reached our criterion for study-wide significance. SNP-based heritability of the HLA variants was small and not significant (h2 = 0.3%, SE = 0.2%). A polygenic score from the case-control genetic association analysis of SNPs in the HLA region did not significantly predict individual differences in intelligence in an independent unselected sample. We conclude that although genetic variation in the HLA region is important to the aetiology of many disorders, it does not appear to be hiding much of the missing heritability of intelligence.

Published
2017

14. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author

Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. 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England [ 150 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 151 ] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA [ 152 ] Beijing Genom Inst, Shenzhen, Peoples R China [ 153 ] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden [ 154 ] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA [ 155 ] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA [ 156 ] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA [ 157 ] Shanghai Inst Prevent Med, Shanghai, Peoples R China [ 158 ] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA [ 159 ] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India [ 160 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 161 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 162 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany [ 163 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 164 ] Sir Charles Gairdner Hosp, Nedlands, WA 6009, 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Subjects
CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Published
2014

15. Common genetic variation near melatonin receptor MTNR1B contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians

Author

Aimo Ruokonen, Jaspal S. Kooner, Delilah Zabaneh, Joban Sehmi, Paul Elliott, James Scott, Piyush Jain, Philippe Froguel, John C. Chambers, Weihua Zhang, Marjo-Riitta Järvelin, David J. Balding, Mark I. McCarthy, and Medical Research Council (MRC)

Subjects
Blood Glucose, Male, Linkage disequilibrium, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Blood Pressure, Type 2 diabetes, CIRCADIAN CLOCK, VARIANTS, 0302 clinical medicine, Risk Factors, POPULATION, 11 Medical and Health Sciences, 2. Zero hunger, 0303 health sciences, education.field_of_study, INSULIN-RESISTANCE, Middle Aged, PREVALENCE, Europe, OBESITY, Hypertension, Original Article, Female, Life Sciences & Biomedicine, Asian Continental Ancestry Group, Adult, medicine.medical_specialty, Population, European Continental Ancestry Group, Blood sugar, India, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Environment, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Endocrinology & Metabolism, Insulin resistance, Asian People, Internal medicine, Internal Medicine, medicine, Genetics, Humans, TOLERANCE, Risk factor, GENOME-WIDE ASSOCIATION, education, Life Style, 030304 developmental biology, Aged, Science & Technology, Receptor, Melatonin, MT2, Genetic Variation, medicine.disease, POLYMORPHISM, Diet, Endocrinology, Diabetes Mellitus, Type 2, FASTING GLUCOSE, Genome-Wide Association Study
Abstract

OBJECTIVE Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians. RESEARCH DESIGN AND METHODS We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians. RESULTS We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 × 10−8, all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 × 10−9), which is in moderate linkage disequilibrium with rs1387153 (r2 = 0.60) and rs10830963 (r2 = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01–0.08) versus 0.05 (0.03–0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06–1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians. CONCLUSIONS Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.

Published
2016

16. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author

Sharon L.R. Kardia, Melinda Mills, Ian J. Deary, Sven Bergmann, Magnus Johannesson, Igor Rudan, Nicholas J. Timpson, Richa Gupta, Hester M. den Ruijter, Rico Rueedi, Lars Bertram, Juliette Harris, Jennifer A. Smith, Eero Kajantie, Jian Yang, David C. Liewald, Ronald de Vlaming, Anu Realo, Jessica D. Faul, Patrik K. E. Magnusson, Jadwiga Buchwald, Philip L. De Jager, Rajesh Rawal, Marisa Koini, K. Petrovic, Unnur Thorsteinsdottir, Pedro Marques-Vidal, Roy Thurik, Evie Stergiakouli, Ivana Kolcic, William G. Iacono, Laura D. Kubzansky, Jaakko Kaprio, Behrooz Z. Alizadeh, Samantha Cherney, Reinhold Schmidt, Vilmundur Gudnason, Nicholas A. Furlotte, Nicholas G. Martin, Delilah Zabaneh, Rebecca T. Emeny, Eco J. C. de Geus, Klaus Berger, Lude Franke, Sven J. van der Lee, S. Fleur W. Meddens, Bart M. L. Baselmans, Dalton Conley, Jouke-Jan Hottenga, David A. Bennett, Saskia Haitjema, Jun Ding, Elina Hyppönen, Kari Stefansson, Henning Tiemeier, Grant W. Montgomery, Michelle N. Meyer, James J. Lee, Aysu Okbay, Lei Yu, Gyda Bjornsdottir, Marie Henrike Geisel, Albertine J. Oldehinkel, Liisa Keltikangas-Järvinen, George Davey Smith, Harold Snieder, Juho Wedenoja, Frits R. Rosendaal, Michel G. Nivard, Simon R. Cox, Christine Power, Dorret I. Boomsma, Börge Schmidt, David A. Hinds, Philipp Koellinger, Harm-Jan Westra, Terho Lehtimäki, Alison Pattie, Jan-Emmanuel De Neve, Torben Hansen, John M. Starr, Albert V. Smith, Antonio Terracciano, Juergen Wellmann, Albert Hofman, Katri Räikkönen, Patrick Turley, Andrew Steptoe, Jimmy Z. Liu, Evelin Mihailov, Jari Lahti, Marika Kaakinen, David R. Weir, Cornelia M. van Duijn, Maciej Trzaskowski, David Cesarini, Najaf Amin, Lydia Quaye, Sara M. Willems, Ghazaleh Fatemifar, Christopher Oldmeadow, Ville Karhunen, Alana Cavadino, Juan R. González, Caroline Hayward, Penelope A. Lind, Tamara B. Harris, Jaime Derringer, Camelia C. Minică, Jacob Gratten, Patrick J. F. Groenen, Ozren Polasek, Anu Loukola, Peter Vollenweider, Christian Gieger, Rodney J. Scott, Lindsay K. Matteson, Meike Bartels, Andrew Bakshi, David Laibson, Andrew C. Heath, Daniel J. Benjamin, Stephen S. Rich, Claire M. A. Haworth, C.A. Hartman, Angelina R. Sutin, Tian Liu, Johan G. Eriksson, Robert Plomin, Francesco Cucca, John Attia, Tarunveer S. Ahluwalia, Andreas J. Forstner, Gudmar Thorleifsson, Rauli Svento, Ute Bültmann, Olli T. Raitakari, Karl-Heinz Jöckel, Mark Alan Fontana, Oliver S. P. Davis, Yong Qian, Anna A. E. Vinkhuyzen, Wei Zhao, Elizabeth G. Holliday, Andres Metspalu, Alexis C. Frazier-Wood, Meena Kumari, Nese Direk, Miriam A. Mosing, Ilja M. Nolte, Sander W. van der Laan, Matt McGue, Tim D. Spector, Marjo-Riitta Järvelin, Peter Eibich, Nancy L. Pedersen, David Schlessinger, Toshiko Tanaka, Dennis O. Mook-Kanamori, Luigi Ferrucci, Gerard Pasterkamp, Jonathan P. Beauchamp, Robert Karlsson, Lenore J. Launer, Helena Schmidt, Renée de Mutsert, Gert G. Wagner, Peter Kraft, Joseph K. Pickrell, Thorkild I. A. Sørensen, André G. Uitterlinden, Patricia A. Boyle, Cornelius A. Rietveld, Robert F. Krueger, Karl-Heinz Ladwig, Michael B. Miller, Sarah E. Medland, Tõnu Esko, Kent D. Taylor, Lavinia Paternoster, Peter J. van der Most, Richard Karlsson Linnér, Laura Pulkki-Råback, Gail Davies, Victoria Garfield, Shun-Chiao Chang, Ruifang Li-Gao, Applied Economics, Pathology, Epidemiology, Public Health, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, Ophthalmology, Social Science Genetic Association Consortium (SSGAC), CHARGE Consortium, Okbay, Aysu, Baselmans, Bart ML, De Neve, Jan-Emmanuel, Turley, Patrick, Hyppönen, Elina, Cesarini, David, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], University of Queensland [Brisbane], Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Tampere University Hospital, University of Turku, King‘s College London, University of Helsinki, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lausanne (UNIL), Birmingham City University (BCU), Helmholtz-Zentrum München (HZM), Department of Epidemiology and Public Health, University College of London [London] (UCL), Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Edinburgh, Florida State University [Tallahassee] (FSU), Wuhan University [China], Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Erasmus University Rotterdam, National Institute for Health and Welfare [Helsinki], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Montpellier Research in Management (MRM), Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Public Health Research (PHR), Sociology/ICS, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and LifeLines Cohort Study

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Disease, Genome-wide association studies, DISEASE, 0302 clinical medicine, well-being, neuroticism, Anxiety Disorders/genetics, Bayes Theorem, Depression/genetics, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Genetics & Heredity, RISK, Genetics, PERSONALITY, [QFIN]Quantitative Finance [q-fin], Depression, HERITABILITY, COMMON VARIANTS, 11 Medical And Health Sciences, Anxiety Disorders, Neuroticism, depression, Behavioural genetics, Life Sciences & Biomedicine, Biology, personality, genetic, epidemiology, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Journal Article, Human height, Subjective well-being, behavioural genetics, METAANALYSIS, Genetic association, HAPPINESS, Science & Technology, MAJOR DEPRESSION, 06 Biological Sciences, Heritability, 030104 developmental biology, genome-wide association studies, HUMAN HEIGHT, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis
Abstract

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

Published
2016

17. Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels

Author

Marjo-Riitta Järvelin, Jaspal S. Kooner, Gonçalo R. Abecasis, Mark N. Wass, Michael J.E. Sternberg, Delilah Zabaneh, Yun Li, Paul Elliott, Clive J. Hoggart, Patrick H. Maxwell, Nelson B. Freimer, Henry K. Bayele, James Scott, Joban Sehmi, Leena Peltonen, Weihua Zhang, Surjit K. S. Srai, John C. Chambers, Mark I. McCarthy, and Aimo Ruokonen

Subjects
Genetics, Nonsynonymous substitution, 0303 health sciences, TMPRSS6, Genome-wide association study, Iron deficiency, Biology, medicine.disease, Article, 03 medical and health sciences, 0302 clinical medicine, Hepcidin, 030220 oncology & carcinogenesis, medicine, biology.protein, SNP, Hemoglobin, Allele, 030304 developmental biology
Abstract

We carried out a genome-wide association study of hemoglobin levels in 16,001 individuals of European and Indian Asian ancestry. The most closely associated SNP (rs855791) results in nonsynonymous (V736A) change in the serine protease domain of TMPRSS6 and a blood hemoglobin concentration 0.13 (95% CI 0.09-0.17) g/dl lower per copy of allele A (P = 1.6 x 10(-13)). Our findings suggest that TMPRSS6, a regulator of hepcidin synthesis and iron handling, is crucial in hemoglobin level maintenance.

Published
2009

18. Gene-centric association signals for haemostasis and thrombosis traits identified with the HumanCVD BeadChip

Author

Juan P. Casas, Fotios Drenos, Meena Kumari, Aroon D. Hingorani, Delilah Zabaneh, Christophe Ladroue, John C. Whittaker, Mika Kivimäki, Anna L. Guyatt, Philippa J. Talmud, Steve E. Humphries, Ian N. M. Day, Tina Shah, Debbie A Lawlor, Gordon D.O. Lowe, Ann Rumley, Tom R. Gaunt, and Sonia Shah

Subjects
0301 basic medicine, Blood Platelets, G-Protein-Coupled Receptor Kinase 5, Blood viscosity, DNA Mutational Analysis, Genome-wide association study, Single-nucleotide polymorphism, Cell Count, Biology, Fibrinogen, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Quantitative Trait, Heritable, Pleiotropy, medicine, Humans, Apolipoproteins A, Genetic Association Studies, Genetic association, Adaptor Proteins, Signal Transducing, Genetics, Clotting factor, Hemostasis, Factor VII, Macrophage Colony-Stimulating Factor, Membrane Transport Proteins, Thrombosis, Hematology, Blood Viscosity, Microarray Analysis, Microspheres, 030104 developmental biology, Phenotype, chemistry, Apolipoprotein A-V, Carrier Proteins, 030217 neurology & neurosurgery, medicine.drug
Abstract

SummaryCoagulation phenotypes show strong intercorrelations, affect cardiovascular disease risk and are influenced by genetic variants. The objective of this study was to search for novel genetic variants influencing the following coagulation phenotypes: factor VII levels, fibrinogen levels, plasma viscosity and platelet count. We genotyped the British Women’s Heart and Health Study (n=3,445) and the Whitehall II study (n=5,059) using the Illumina HumanCVD BeadArray to investigate genetic associations and pleiotropy. In addition to previously reported associations (SH2B3, F7/F10, PROCR, GCKR, FGA/FGB/FGG, IL5), we identified novel associations at GRK5 (rs10128498, p = 1.30×10−6), GCKR (rs1260326, p = 1.63×10−6), ZNF259-APOA5 (rs651821, p = 7.17x10–6) with plasma viscosity; and at CSF1 (rs333948, p = 8.88×10−6) with platelet count. A pleiotropic effect was identified in GCKR which associated with factor VII (p = 2.16×10−7) and plasma viscosity (p = 1.63×10−6), and, to a lesser extent, ZNF259-APOA5 which also associated with factor VII and fibrinogen (p

Published
2013

19. Population Genomics of Cardiometabolic Traits: Design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium

Author

Tina Shah, Jorgen Engmann, Caroline Dale, Sonia Shah, Jon White, Claudia Giambartolomei, Stela McLachlan, Delilah Zabaneh, Alana Cavadino, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom Gaunt, Michael V Holmes, Helen Warren, Daniel I Swerdlow, Teri-Louise Davies, Fotios Drenos, Jackie Cooper, Reecha Sofat, Mark Caulfield, Shah Ebrahim, Debbie A Lawlor, Philippa J Talmud, Steve E Humphries, Christine Power, Elina Hypponen, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Claudia Langenberg, Yoav Ben-Shlomo, Ian N Day, Peter Whincup, Richard Morris, Mark W J Strachan, Jacqueline Price, Meena Kumari, Mika Kivimaki, Vincent Plagnol, Frank Dudbridge, John C Whittaker, Juan P Casas, Aroon D Hingorani, UCLEB Consortium, Shah, Tina, Engmann, Jorgen, Dale, Caroline, Shah, Sonia, Hypponen, Elina, Hingorani, Aroon D, and The UCLEB Consortium

Subjects
Gerontology, Research design, Male, Epidemiology, lcsh:Medicine, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular, Population genomics, 0302 clinical medicine, cohort studies, cardiovascular disease, Risk Factors, Health care, Medicine, Longitudinal Studies, lcsh:Science, Oligonucleotide Array Sequence Analysis, Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, Multidisciplinary, Middle Aged, 3. Good health, Cardiovascular Diseases, Research Design, Genetic Epidemiology, Female, Metabolic Networks and Pathways, Cohort study, Research Article, Adult, Genetic Markers, General Science & Technology, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, MD Multidisciplinary, Humans, UCLEB Consortium, Risk factor, education, Biology, Cardiovascular Disease Epidemiology, Genetic Association Studies, 030304 developmental biology, Aged, Evolutionary Biology, Population Biology, business.industry, Genome, Human, lcsh:R, biomarkers, genetic loci, Computational Biology, lcsh:Q, Metagenomics, business, Population Genetics, Genome-Wide Association Study
Abstract

Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.

Published
2013

20. Correction: Population Genomics of Cardiometabolic Traits: Design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium

Author

Tina Shah, Jorgen Engmann, Caroline Dale, Sonia Shah, Jon White, Claudia Giambartolomei, Stela McLachlan, Delilah Zabaneh, Alana Cavadino, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom Gaunt, Michael V. Holmes, Helen Warren, Teri-Louise Davies, Fotios Drenos, Jackie Cooper, Reecha Sofat, Mark Caulfield, Shah Ebrahim, Debbie A. Lawlor, Philippa J. Talmud, Steve E. Humphries, Christine Power, Elina Hypponen, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Yoav Ben-Shlomo, Ian N. Day, Peter Whincup, Richard Morris, Mark W. J. Strachan, Jacqueline Price, Meena Kumari, Mika Kivimaki, Vincent Plagnol, Frank Dudbridge, John C. Whittaker, Juan P. Casas, and Aroon D. Hingorani

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Multidisciplinary, lcsh:R, Correction, lcsh:Medicine, 030209 endocrinology & metabolism, lcsh:Q, lcsh:Science, 030304 developmental biology
Published
2013

21. Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk

Author

Gualtiero I. Colombo, Jacqueline C. M. Witteman, Christopher J. O'Donnell, Damiano Baldassarre, Göran K. Hansson, Martin Farrall, Sonia Shah, Steve E. Humphries, Kai Savonen, Anders Hamsten, Lasse Folkersen, Per Eriksson, Philippe Giral, Pierre Fontanillas, Albert Hofman, Aroon D. Hingorani, Bruna Gigante, Maria Grazia Franzosi, Udo Seedorf, Anders Gabrielsen, Meena Kumari, Philippa J. Talmud, Fabrizio Veglia, Jennifer L. Bolton, Ann-Christine Syvänen, Jacqueline F. Price, Nilesh J. Samani, Elmo Mannarino, Ulf de Faire, Mika Kivimäki, Kristiina Nyyssönen, Andries J. Smit, Elena Tremoli, Robert Clarke, Christine Robertson, Delilah Zabaneh, André G. Uitterlinden, Angela Silveira, Tomi-Pekka Tuomainen, Bo Hedblad, Nicholas J. Wareham, Hugh Watkins, Malin Larsson, Muredach P. Reilly, Claudia Langenberg, Max Vikström, Bengt Sennblad, Olle Melander, John E. Deanfield, Karl Gertow, Benjamin F. Voight, John Öhrvik, Maryam Kavousi, Maria Sabater-Lleal, Karin Leander, Jeanette Erdmann, Rona J. Strawbridge, Anders Franco-Cereceda, Rainer Rauramaa, Stela McLachlan, Ulf Hedin, Cristiano Fava, Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Epidemiology, and Internal Medicine

Subjects
Male, Pathology, Genome-wide association study, 030204 cardiovascular system & hematology, SUSCEPTIBILITY, ultrasounds, Coronary artery disease, Cohort Studies, 0302 clinical medicine, Risk Factors, Medicine, genetics, Myocardial infarction, Carotid intima-media thickness, Genetics (clinical), 0303 health sciences, education.field_of_study, CARDIOVASCULAR RISK, Nuclear Proteins, Middle Aged, Phenotype, Cardiology, cardiovascular system, Female, BCAR1-CFDP1-TMEM170A locus, Cardiology and Cardiovascular Medicine, coronary artery disease, medicine.medical_specialty, Population, Locus (genetics), WHITEHALL-II, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, GENOME-WIDE ASSOCIATION, education, Alleles, METAANALYSIS, 030304 developmental biology, Aged, business.industry, Gene Expression Profiling, Membrane Proteins, Reproducibility of Results, Odds ratio, medicine.disease, Phosphoproteins, ROTTERDAM, CALCIFICATION, VASCULAR SMOOTH-MUSCLE, Minor allele frequency, Crk-Associated Substrate Protein, Intima-media thickness, Gene Expression Regulation, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Genetic Loci, business
Abstract

Background— Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results— To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT mean , IMT max , and IMT mean-max ), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1 ) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P =6.75×10 −7 for IMT max ; replication P =7.24×10 −6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort ( P =0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P =6.53×10 −6 , n=13 591; and 0.95 [0.92–0.98], P =1.83×10 −4 , n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138). Conclusions— This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

Published
2012

22. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Author

Sarah Edkins, Anubha Mahajan, Nita G. Forouhi, Danish Saleheen, Lori L. Bonnycastle, Jackie F. Price, Lu Qi, Jasmina Kravic, Laura J. Scott, Susanne Moebus, Timothy M. Frayling, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Lars Lind, James F. Wilson, John Beilby, Emil Rehnberg, Veikko Salomaa, Richard N. Bergman, Thomas Illig, Ruth J. F. Loos, Martina Müller-Nurasyid, Andrew Crenshaw, Karl-Heinz Jöckel, Krista Fischer, James B. Meigs, Rob M. van Dam, George Dedoussis, Christopher J. Groves, Julia Meyer, Valur Emilsson, Timo Saaristo, Kees Hovingh, Joseph Trakalo, Peter Kraft, André G. Uitterlinden, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Denis Rybin, Gonçalo R. Abecasis, Andrew T. Hattersley, Sonia Shah, Bruna Gigante, Jaakko Tuomilehto, Pierre Fontanillas, Kay-Tee Khaw, Annette Peters, Andrew D. Johnson, Rafn Benediktsson, Candace Guiducci, Andrew P. Morris, Tõnu Esko, Bo Isomaa, Anne U. Jackson, Beverley Balkau, Peter Donnelly, Thomas W. Mühleisen, Barbara Thorand, Tom Wilsgaard, Alan R. Shuldiner, David J. Hunter, Roman Wennauer, Karl Gertow, Wen Hong L. Kao, Alan James, Cordelia Langford, Christian Herder, Timo A. Lakka, Soumya Raychaudhuri, Jian'an Luan, Katharine R. Owen, Jennie Hui, Francis S. Collins, Juha Saltevo, David Couper, Bernhard O. Boehm, Sonali Pechlivanis, Raimund Erbel, Suthesh Sivapalaratnam, Markku Laakso, Augustine Kong, Heather M. Stringham, Leena Kinnunen, Kathleen Stirrups, Markus M. Nöthen, Ashok Kumar, Andrew R. Wood, Delilah Zabaneh, Rona J. Strawbridge, Bill Musk, Noël P. Burtt, Eeva Korpi-Hyövälti, Oddgeir L. Holmen, Inga Prokopenko, Marilyn C. Cornelis, Elodie Eury, Angela Silveira, Inês Barroso, Michael Roden, Unnur Thorsteinsdottir, Josée Dupuis, Han Chen, Cornelia M. van Duijn, Samuli Ripatti, Anna Jonsson, Gerald Steinbach, George B. Grant, Kristian Hveem, Andres Metspalu, Astradur B. Hreidarsson, Guillaume Charpentier, John Danesh, Claudia Langenberg, Sirkka Keinänen-Kiukaanniemi, Christian Dina, James S. Pankow, Panos Deloukas, Rainer Rauramaa, Satu Männistö, Kaarel Krjutškov, Eric Boerwinkle, Wendy Winckler, Valeriya Lyssenko, Anders Hamsten, Philippe Froguel, Nancy L. Pedersen, Harry Campbell, Sailaja Vedantam, Nicholas J. Wareham, Hassan Khan, Simon C. Potter, Damiano Baldassarre, Tiinamaija Tuomi, Vasiliki Lagou, Mozhgan Dorkhan, Stavroula Kanoni, Benjamin F. Voight, Wolfgang Rathmann, Tanya M. Teslovich, Antigone S. Dimas, Bengt Sennblad, Olle Melander, Albert Hofman, Mark I. McCarthy, Andrew D. Morris, Fabrizio Veglia, Karen L. Mohlke, Melissa Parkin, Sarah E. Hunt, Frank B. Hu, Elena Tremoli, Gudmar Thorleifsson, Steve E. Humphries, Jason Carey, Eero Lindholm, Alex S. F. Doney, Peter Almgren, Erik Ingelsson, Colin N. A. Palmer, Johanna Kuusisto, Inger Njølstad, Ann-Christine Syvänen, Leena Peltonen, Eric J.G. Sijbrands, Ross M. Fraser, Mieke D. Trip, Ghazala Mirza, Robert W. Lawrence, Neil Robertson, David Altshuler, Harald Grallert, Gunnar Sigurðsson, Kari Stefansson, N. William Rayner, Johan G. Eriksson, Christian Gieger, Emmi Tikkanen, Mustafa Atalay, S Wiltshire, Eleftheria Zeggini, Alena Stančáková, Loukianos S. Rallidis, Jouko Saramies, Stéphane Lobbens, Man Li, Hyun Min Kang, Loic Yengo, Norman Klopp, Ayellet V. Segrè, Carl G. P. Platou, Tom Forsén, Qi Sun, Karin Leander, Caroline S. Fox, Sekar Kathiresan, Jose C. Florez, Leif Groop, Teresa Ferreira, John R. B. Perry, Ulf de Faire, Peter S. Chines, Elizabeth J. Rossin, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Surgery, Dermatology, Epidemiology, and Internal Medicine

Subjects
Male, Linkage disequilibrium, Medizin, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, Genetic Predisposition to Disease, Pakistan, Gene, 030304 developmental biology, Genetic association, 0303 health sciences, Case-control study, medicine.disease, Genetic architecture, 3. Good health, Diabetes Mellitus, Type 2, Genes, Evolutionary biology, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.

Published
2012

23. A gene-centric study of common carotid artery remodelling

Author

Seamus C. Harrison, Ann-Christine Syvänen, Aroon D. Hingorani, Obi Agu, Jan D. Blankensteijn, Anders Hamsten, Rona J. Strawbridge, Gert J. de Borst, Ulf de Faire, Lasse Folkersen, Gerry Fowkes, Mika Kivimäki, Karl Gertow, Elena Tremoli, Ionna Tzoulaki, Kristiina Nyyssönen, John E. Deanfield, Sonia Shah, Delilah Zabaneh, Fabrizio Veglia, Folkert W. Asselbergs, Andre M. van Rij, Bengt Sennblad, Philippa J. Talmud, Steve E. Humphries, Sita H. Vermeulen, Matthew J. Bown, Rainer Rauramaa, Suzanne Holewijn, Anders Franco-Cereceda, Gregory T. Jones, Jacqueline F. Price, Andries J. Smit, Per-Olof Eriksson, Annette F. Baas, Elmo Mannarino, Damiano Baldassarre, Nicholas J. Wareham, Philippe Giral, Meena Kumari, Yolanda van der Graaf, Bruna Gigante, Fotios Drenos, Jacqueline de Graaf, Angela Silveira, Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Surgery, and ICaR - Ischemia and repair

Subjects
Male, Vascular remodelling, Pathology, Genome-wide association study, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, Carotid Intima-Media Thickness, INTIMA-MEDIA THICKNESS, Genome-wide association studies, 0302 clinical medicine, Medicine, Common carotid artery, RISK, 0303 health sciences, Middle Aged, Phenotype, Chromosomes, Human, Pair 1, CARDIOVASCULAR-DISEASE, 2ND MANIFESTATIONS, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Carotid Artery, Common, Polymorphism, Single Nucleotide, Article, Vascular remodelling in the embryo, 03 medical and health sciences, medicine.artery, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Gene, Genetic Association Studies, Health aging / healthy living Cardiovascular diseases [IGMD 5], METAANALYSIS, 030304 developmental biology, Aged, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], ABDOMINAL AORTIC-ANEURYSM, business.industry, DIAMETER, Carotid artery.common, Blood pressure, Intima-media thickness, ATHEROSCLEROSIS, Abdominal aortic aneurysm, business, Expansive, Carotid artery, Aortic Aneurysm, Abdominal
Abstract

Background Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08–0.18 mm, P = 8.2 × 10−8). A proxy SNP (rs4916251, R2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case–control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03–1.17, p = 2.8 × 10−3, I2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development., Highlights ► In the IMPROVE study (n > 3000) variants at 1q24.3 were strongly associated with larger carotid diameters. ► The lead variant was associated with Abdominal Aortic Aneurysm (AAA) in meta-analysis of 5 studies (n > 50,000). ► Variants at 1q24.3 appear to be associated with vascular remodelling and risk of AAA.

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24. Phenome-wide analysis of genome-wide polygenic scores

Author

Kaili Rimfeld, Paul F. O'Reilly, Delilah Zabaneh, Eva Krapohl, Pingault J, Jack Euesden, S. von Stumm, Gerome Breen, Robert Plomin, and Philip S. Dale

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Adolescent, BF Psychology, media_common.quotation_subject, Intelligence, education, QH426 Genetics, Phenome, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Personality, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetic Association Studies, media_common, Behavior, business.industry, Depression, Cognition, Explained variation, United Kingdom, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Phenotype, Behavioral medicine, Predictive power, Global Positioning System, Schizophrenia, Female, Original Article, Psychology, business, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Psychopathology, Clinical psychology, Forecasting, Genome-Wide Association Study
Abstract

Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia, depression and dementia) and cognitive traits (for example, intelligence, educational attainment and intracranial volume). The behavioral phenome included 50 traits from the domains of psychopathology, personality, cognitive abilities and educational achievement. We examined phenome-wide profiles of associations for the entire distribution of each GPS and for the extremes of the GPS distributions. The cognitive GPS yielded stronger predictive power than the psychiatric GPS in our UK-representative sample of adolescents. For example, education GPS explained variation in adolescents’ behavior problems (~0.6%) and in educational achievement (~2%) but psychiatric GPS were associated with neither. Despite the modest effect sizes of current GPS, quantile analyses illustrate the ability to stratify individuals by GPS and opportunities for research. For example, the highest and lowest septiles for the education GPS yielded a 0.5 s.d. difference in mean math grade and a 0.25 s.d. difference in mean behavior problems. We discuss the usefulness and limitations of GPS based on adult GWAS to predict genetic propensities earlier in development.

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