Meta-Analysis

. 2013 Apr 1;73(7):667-78.

doi: 10.1016/j.biopsych.2012.09.033. Epub 2013 Jan 3.

A genome-wide association study of depressive symptoms

Karin Hek^#¹, Ayse Demirkan^#¹, Jari Lahti^#¹, Antonio Terracciano^#¹, Alexander Teumer^#¹, 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, Cornelia M van Duijn^#¹, Hans J Grabe^#¹, Lenore J Launer^#¹, Kathryn L Lunetta^#¹, Thomas H Mosley Jr^#¹, Anne B Newman^#¹, Henning Tiemeier^#¹, Joanne Murabito^#¹

Affiliations

Affiliation

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.

^# Contributed equally.

PMID: 23290196
PMCID: PMC3845085
DOI: 10.1016/j.biopsych.2012.09.033

Meta-Analysis

A genome-wide association study of depressive symptoms

Karin Hek et al. Biol Psychiatry. 2013.

. 2013 Apr 1;73(7):667-78.

doi: 10.1016/j.biopsych.2012.09.033. Epub 2013 Jan 3.

Authors

Affiliation

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.

^# Contributed equally.

PMID: 23290196
PMCID: PMC3845085
DOI: 10.1016/j.biopsych.2012.09.033

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.

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Figures

**Figure 1**
Association results in the 5q21 region. Summary of the association of single nucleotide polymorphisms (SNPs) on chromosome 5 (base 103,500,000 to 104,500,000) with depressive symptoms from the overall meta-analysis (n = 51,258). The SNP with the strongest association (rs40465) is highlighted in blue and its corresponding p value is given. Other SNPs are colored according to their degree of linkage disequilibrium (LD) with rs40465, ranging from high LD (orange, R² .5–1.0) to low LD (white, R² < .2). cM, centimorgan; kb, kilobase; Mb, megabase.

See this image and copyright information in PMC

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A genome-wide association study of depressive symptoms

Affiliation

A genome-wide association study of depressive symptoms

Authors

Affiliation

Abstract

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical