title: Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.
abstract: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.
  
  
  
  We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).
  
  
  
  One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity.
  
  
  
  Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
authors.affiliation: Genetic Epidemiology Unit,Departments of Epidemiology and Clinical Genetics,Erasmus MC,Rotterdam,The Netherlands.
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authors.lastname: Demirkan
authors.affiliation: Institute of Behavioural Sciences, University of Helsinki,Helsinki,Finland.
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authors.lastname: Lahti
authors.affiliation: Department of Epidemiology,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics,Karolinska Institute,Stockholm,Sweden.
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authors.lastname: Viktorin
authors.affiliation: Department of Biostatistics,Boston University School of Public Health,Boston, MA,USA.
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authors.affiliation: National Institute on Aging, National Institutes of Health,Baltimore, MD,USA.
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authors.affiliation: Laboratory of Neurogenetics,National Institute on Aging, National Institutes of Health,Bethesda, MD,USA.
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authors.affiliation: National Institute on Aging, National Institutes of Health,Baltimore, MD,USA.
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authors.affiliation: Department of Epidemiology,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Institute of Epidemiology and Social Medicine, University of Münster,Münster,Germany.
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authors.affiliation: Public Health Genomics Unit and Institute for Molecular Medicine Finland (FIMM),National Institute for Health and Welfare,Helsinki,Finland.
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authors.affiliation: Department of Neurological Sciences,Rush Alzheimer's Disease Center, Rush University Medical Center,Chicago,IL,USA.
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authors.affiliation: Department of Epidemiology,University of Michigan,Ann Arbor,MI,USA.
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authors.affiliation: University of Exeter Medical School,Exeter,UK.
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authors.affiliation: Genetic Epidemiology Unit,Departments of Epidemiology and Clinical Genetics,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,Cambridge,UK.
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authors.affiliation: Department of Preventive Medicine and Public Health,School of Medicine, Creighton University,Omaha,NE,USA.
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authors.initials: WV
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authors.affiliation: National Institute on Aging, National Institutes of Health,Baltimore, MD,USA.
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authors.affiliation: Survey Research Center, Institute for Social Research, University of Michigan,Ann Arbor,MI,USA.
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authors.affiliation: National Institute on Aging, National Institutes of Health,Baltimore, MD,USA.
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authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR,Monserrato,Cagliari,Italy.
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authors.affiliation: Department of Epidemiology,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Department of Epidemiology,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Department of Epidemiology,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Public Health Genomics Unit and Institute for Molecular Medicine Finland (FIMM),National Institute for Health and Welfare,Helsinki,Finland.
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authors.affiliation: Survey Research Center, Institute for Social Research, University of Michigan,Ann Arbor,MI,USA.
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authors.affiliation: Department of Chronic Disease Prevention,National Institute for Health and Welfare,Helsinki,Finland.
authors.forename: V
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authors.affiliation: Department of Epidemiology,Erasmus MC,Rotterdam,The Netherlands.
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authors.forename: Y
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authors.affiliation: Department of Medical Epidemiology and Biostatistics,Karolinska Institute,Stockholm,Sweden.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics,Karolinska Institute,Stockholm,Sweden.
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authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki,Helsinki,Finland.
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authors.affiliation: University of Exeter Medical School,Exeter,UK.
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authors.affiliation: Department of Epidemiology,Mailman School of Public Health, Columbia University,New York,NY,USA.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics,Karolinska Institute,Stockholm,Sweden.
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authors.affiliation: National Institute on Aging, National Institutes of Health,Baltimore, MD,USA.
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authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR,Monserrato,Cagliari,Italy.
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authors.affiliation: Genetic Epidemiology Unit,Departments of Epidemiology and Clinical Genetics,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Department of Neurological Sciences,Rush Alzheimer's Disease Center, Rush University Medical Center,Chicago,IL,USA.
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authors.affiliation: Public Health Genomics Unit and Institute for Molecular Medicine Finland (FIMM),National Institute for Health and Welfare,Helsinki,Finland.
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authors.affiliation: Institute of Epidemiology and Social Medicine, University of Münster,Münster,Germany.
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authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry,National Institute on Ageing, National Institutes of Health,Bethesda,MD,USA.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics,Karolinska Institute,Stockholm,Sweden.
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authors.affiliation: Department of Medicine, Section of General Internal Medicine,Boston University School of Medicine,Boston,MA,USA.
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authors.affiliation: Department of Epidemiology,Erasmus MC,Rotterdam,The Netherlands.
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authors.affiliation: Genetic Epidemiology Unit,Departments of Epidemiology and Clinical Genetics,Erasmus MC,Rotterdam,The Netherlands.
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mesh_terms: D003863:Depression / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D044122:Receptor, Melatonin, MT1 / Q000235:genetics*; D013001:Somatoform Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology
chemical_list: C000610981:MTNR1A protein, human; D044122:Receptor, Melatonin, MT1
keywords: Genome-wide association studies; major depressive disorder; meta-analyses