Karin Hek1, Ayse Demirkan1, Jari Lahti1, Antonio Terracciano1, Alexander Teumer1, Cornelia M van Duijn1, Hans J Grabe1, Lenore J Launer1, Kathryn L Lunetta1, Thomas H Mosley1, Anne B Newman1, Henning Tiemeier1, Joanne Murabito1, Marilyn C Cornelis1, Najaf Amin1, Erin Bakshis1, Jens Baumert1, Jingzhong Ding1, Yongmei Liu1, Kristin Marciante1, Osorio Meirelles1, Michael A Nalls1, Yan V Sun1, Nicole Vogelzangs1, Lei Yu1, Stefania Bandinelli1, Emelia J Benjamin1, David A Bennett1, Dorret Boomsma1, Alessandra Cannas1, Laura H Coker1, Eco de Geus1, Philip L De Jager1, Ana V Diez-Roux1, Shaun Purcell1, Frank B Hu1, Eric B Rimma1, David J Hunter1, Majken K Jensen1, Gary Curhan1, Kenneth Rice1, Alan D Penman1, Jerome I Rotter1, Nona Sotoodehnia1, Rebecca Emeny1, Johan G Eriksson1, Denis A Evans1, Luigi Ferrucci1, Myriam Fornage1, Vilmundur Gudnason1, Albert Hofman1, Thomas Illig1, Sharon Kardia1, Margaret Kelly-Hayes1, Karestan Koenen1, Peter Kraft1, Maris Kuningas1, Joseph M Massaro1, David Melzer1, Antonella Mulas1, Cornelis L Mulder1, Anna Murray1, Ben A Oostra1, Aarno Palotie1, Brenda Penninx1, Astrid Petersmann1, Luke C Pilling1, Bruce Psaty1, Rajesh Rawal1, Eric M Reiman1, Andrea Schulz1, Joshua M Shulman1, Andrew B Singleton1, Albert V Smith1, Angelina R Sutin1, André G Uitterlinden1, Henry Völzke1, Elisabeth Widen1, Kristine Yaffe1, Alan B Zonderman1, Francesco Cucca1, Tamara Harris1, Karl-Heinz Ladwig1, David J Llewellyn1, Katri Räikkönen1, Toshiko Tanaka1. 1. Research Centre O3 (KH, CLM, HT), Department of Psychiatry, and Department of Epidemiology (KH, AH, MK, AGU, HT), Erasmus MC, Rotterdam, The Netherlands; Institute of Behavioural Sciences (JL, KRa), University of Helsinki, Helsinki, Finland; Clinical Research Branch (TT), National Institute on Aging, Baltimore, Maryland; Interfaculty Institute for Genetics and Functional Genomics (ATeu), University Medicine Greifswald, Greifswald, Germany; Department of Nutrition (MCC, FBH, EBR, MKJ), Harvard School of Public Health, Boston, Massachusetts; Department of Epidemiology (EB, AVD-R, SK), University of Michigan School of Public Health, Ann Arbor, Michigan; Institute of Epidemiology II (JB, RE, K-HL), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Department of Internal Medicine (JD), Division of Geriatrics, and Department of Epidemiology and Prevention (YL), Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina; Department of Medicine (KM), Cardiovascular Health Research Unit, University of Washington, Seattle, Washington; National Institute on Aging (ATer, OM, ARS), National Institutes of Health, Department of Health and Human Services, Baltimore; and Laboratory of Neurogenetics (MAN, ABS), Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland; Department of Epidemiology (YVS), Emory University, Atlanta, Georgia; EMGO Institute for Health and Care Research (NV, BPe), and Department of Psychiatry (NV, BPe), VU University Medical Center, Amsterdam, The Netherlands; Rush Alzheimer's Disease Center (LY, DAB), and Department of Neurological Sciences (LY, DAB), Rush University Medical Center, Chicago, Illinois; Geriatric Unit Azienda Sanitaria di Firenze (SB), Firenze, Italy; National Heart, Lung, and Blood Institute's Framingham Heart Study (EJB, MK-H, JMM, KLL, JM), Framingham; and Department of Medicine (EJB), Section of Cardiology and Preventive Medicine, Boston University School of Medicine and Public Health, Boston, Massachusetts; Department of Biological Psychology (DB, EdG), VU University, Amsterdam, The Netherlands; Istituto di Ricerca Genetica e Biomedica (AC, AMul, FC), Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy; Division of Public Health Sciences (LHC), Wake Forest School of Medicine, Winston-Salem, North Carolina; Department of Neurology (PLDJ), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital, Harvard Medical School, Boston; Department of Psychiatry (SP), Massachusetts General Hospital and Harvard Medical School, Boston, and the Broad Institute, Cambridge; and Department of Epidemiology (FBH, EBR), Harvard School of Public Health, Boston, Massachusetts; Department of Biostatistics (KRi), University of Washington, Seattle, Washington; Center of Biostatistics and Department of Medicine (ADP), University of Mississippi Medical Center, Jackson, Mississippi; Medical Genetics Institute (JIR), Cedars Sinai Medical Center, Los Angeles, California; Division of Cardiology (NS), and Cardiovascular Health Research Unit (NS), Department of Medicine, University of Washington, Seattle, Washington; National Institute for Health and Welfare (JGE); Department of General Practice and Primary Health Care (JGE), University of Helsinki; Unit of General Practice (JGE), Helsinki University Central Hospital; and Folkhalsan Research Centre (JGE), Helsinki; and Vasa Central Hospital (JGE), Vasa, Finland; Department of Internal Medicine (DAE), Rush Institute for Health Aging, Rush University Medical Center, Chicago, Illinois; Longitudinal Studies Section (LF), Clinical Research Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland; Brown Foundation Institute of Molecular Medicine (MF), University of Texas Health Science Center at Houston, Houston, Texas; Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging (AH, AGU, CMvD, HT), Leiden, The Netherlands; Research Unit of Molecular Epidemiology (TI), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Department of Neurology (MK-H), Boston University School of Medicine, Boston, Massachusetts; Department of Epidemiology (KK), Mailman School of Public Health, Columbia University, New York, New York; Department of Biostatistics (JMM), Boston University School of Public Health, Boston, Massachusetts; Epidemiology and Public Health (DM, LCP, DJL), Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom; Center for Medical Systems Biology (CMvD), Leiden, The Netherlands; Institute of Biomedical and Clinical Sciences (AMur), Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom; Mental Health Center BavoEuropoort (CLM), and Department of Clinical Genetics (BAO), Erasmus MC, Rotterdam, The Netherlands; Wellcome Trust Sanger Institute (APa), Wellcome Trust Genome Campus, Cambridge, United Kingdom; Institute for Molecular Medicine Finland (APa, EW), University of Helsinki, and Department of Medical Genetics (APa), University of Helsinki and University Central Hospital, Helsinki, Finland; Program in Medical and Population Genetics and Genetics Analysis Platform (APa), The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts; Department of Psychiatry (BPe), Leiden University Medical Centre, Leiden, and Department of Psychiatry (BPe), University Medical Centre Groningen, Groningen, The Netherlands; Institute of Clinical Chemistry and Laboratory Medicine (APe), University Medicine Greifswald, Greifswald, Germany; Cardiovascular Health Research Unit (BPs), Departments of Medicine, Epidemiology, and Health Services, University of Washington, and Group Health Research Institute (BPs), Group Health Cooperative, Seattle, Washington; Institute of Genetic Epidemiology (RR), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Neurogenomics Division (EMR), Translational Genomics Research Institute, and Banner Alzheimer's Institute (EMR), Phoenix, Arizona; Department of Psychiatry and Psychotherapy (AS, HJG), University Medicine Greifswald, Helios-Hospital, Stralsund, Germany; Laboratory of Behavioral Neuroscience (ABZ), National Institute on Aging, Baltimore, Maryland; Department of Internal Medicine (AGU), Erasmus MC, Rotterdam, The Netherlands; Institute for Community Medicine (HV), University Medicine Greifswald, Germany; Department of Psychiatry (KY), University of California San Francisco, San Francisco, California; Icelandic Heart Association (VG, AVS), Kopavogur, Iceland; Departments of Neurology (KY) and Epidemiology and Biostatistics (KY), University of California San Francisco, San Francisco, California; Laboratory of Epidemiology, Demography and Biometry (TH, LJL), National Institute on Aging, Bethesda, Maryland; Department of Biostatistics (KLL), Boston University School of Public Health, Boston, Massachusetts; Department of Medicine (THM), University of Mississippi Medical Center, Jackson, Mississippi; Department of Medicine (JM), Section of General Internal Medicine, Boston University School of Medicine; Program in Molecular and Genetic Epidemiology (DJH, PK), Harvard School of Public Health; and Brigham and Women's Hospital (GC), Harvard Medical School, Boston, Massachusetts; Department of Epidemiology (ABN), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Medicine (VG, AVS), University of Iceland, Reykjavik, Iceland; Hannover Unified Biobank (TI), Hannover Medical School, Hannover, Germany; College of Medicine (ATer, ARS), Florida State University, Tallahassee, Florida; Genetic Epidemiology Unit (AD, NA, BAO, CMvD), Departments of Epidemiology and Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands; and Departments of Neurology and Molecular Human Genetics (JMS), Baylor College of Medicine, Houston, Texas.
Abstract
BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
BACKGROUND:Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
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