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Genome-wide meta-analysis of depression in 807,553 individuals identifies 102 independent variants with replication in a further 1,507,153 individuals

View ORCID ProfileDavid M. Howard, View ORCID ProfileMark J. Adams, View ORCID ProfileToni-Kim Clarke, Jonathan D. Hafferty, View ORCID ProfileJude Gibson, View ORCID ProfileMasoud Shirali, View ORCID ProfileJonathan R. I. Coleman, Joey Ward, View ORCID ProfileEleanor M. Wigmore, Clara Alloza, View ORCID ProfileXueyi Shen, View ORCID ProfileMiruna C. Barbu, Eileen Y. Xu, View ORCID ProfileHeather C. Whalley, Riccardo E. Marioni, View ORCID ProfileDavid J. Porteous, Gail Davies, View ORCID ProfileIan J. Deary, Gibran Hemani, Chao Tian, View ORCID ProfileDavid A. Hinds, 23andMe Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, View ORCID ProfileMaciej Trzaskowski, View ORCID ProfileEnda M. Byrne, View ORCID ProfileStephan Ripke, View ORCID ProfileDaniel J. Smith, View ORCID ProfilePatrick F. Sullivan, View ORCID ProfileNaomi R. Wray, View ORCID ProfileGerome Breen, View ORCID ProfileCathryn M. Lewis, View ORCID ProfileAndrew M. McIntosh
doi: https://doi.org/10.1101/433367
David M. Howard
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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  • For correspondence: D.Howard@ed.ac.uk
Mark J. Adams
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Toni-Kim Clarke
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Jonathan D. Hafferty
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Jude Gibson
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Masoud Shirali
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Jonathan R. I. Coleman
2Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK
3NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Trust, London, UK
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Joey Ward
4Institute of Health and Wellbeing, University of Glasgow, UK
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Eleanor M. Wigmore
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Clara Alloza
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Xueyi Shen
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Miruna C. Barbu
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Eileen Y. Xu
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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Heather C. Whalley
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
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  • ORCID record for Heather C. Whalley
Riccardo E. Marioni
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
6Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
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David J. Porteous
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
6Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
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Gail Davies
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
7Department of Psychology, University of Edinburgh, Edinburgh, UK
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Ian J. Deary
5Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
7Department of Psychology, University of Edinburgh, Edinburgh, UK
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Gibran Hemani
8Medical Research Council (MRC) Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
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Chao Tian
923andMe, Inc., Mountain View, CA, USA
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David A. Hinds
923andMe, Inc., Mountain View, CA, USA
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923andMe, Inc., Mountain View, CA, USA
Maciej Trzaskowski
10Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
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Enda M. Byrne
10Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
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Stephan Ripke
11Department of Psychiatry, Charite Universitatsmedizin Berlin Campus Benjamin Franklin, Berlin, Germany
12Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
13Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Daniel J. Smith
4Institute of Health and Wellbeing, University of Glasgow, UK
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Patrick F. Sullivan
14Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
15Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
16Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
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Naomi R. Wray
10Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
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Gerome Breen
2Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK
3NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Trust, London, UK
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Cathryn M. Lewis
2Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK
3NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Trust, London, UK
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Andrew M. McIntosh
1Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
7Department of Psychology, University of Edinburgh, Edinburgh, UK
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Abstract

Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,507,153 individuals (474,574 cases and 1,032,579 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

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Posted October 09, 2018.
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Genome-wide meta-analysis of depression in 807,553 individuals identifies 102 independent variants with replication in a further 1,507,153 individuals
David M. Howard, Mark J. Adams, Toni-Kim Clarke, Jonathan D. Hafferty, Jude Gibson, Masoud Shirali, Jonathan R. I. Coleman, Joey Ward, Eleanor M. Wigmore, Clara Alloza, Xueyi Shen, Miruna C. Barbu, Eileen Y. Xu, Heather C. Whalley, Riccardo E. Marioni, David J. Porteous, Gail Davies, Ian J. Deary, Gibran Hemani, Chao Tian, David A. Hinds, 23andMe Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Maciej Trzaskowski, Enda M. Byrne, Stephan Ripke, Daniel J. Smith, Patrick F. Sullivan, Naomi R. Wray, Gerome Breen, Cathryn M. Lewis, Andrew M. McIntosh
bioRxiv 433367; doi: https://doi.org/10.1101/433367
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Genome-wide meta-analysis of depression in 807,553 individuals identifies 102 independent variants with replication in a further 1,507,153 individuals
David M. Howard, Mark J. Adams, Toni-Kim Clarke, Jonathan D. Hafferty, Jude Gibson, Masoud Shirali, Jonathan R. I. Coleman, Joey Ward, Eleanor M. Wigmore, Clara Alloza, Xueyi Shen, Miruna C. Barbu, Eileen Y. Xu, Heather C. Whalley, Riccardo E. Marioni, David J. Porteous, Gail Davies, Ian J. Deary, Gibran Hemani, Chao Tian, David A. Hinds, 23andMe Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Maciej Trzaskowski, Enda M. Byrne, Stephan Ripke, Daniel J. Smith, Patrick F. Sullivan, Naomi R. Wray, Gerome Breen, Cathryn M. Lewis, Andrew M. McIntosh
bioRxiv 433367; doi: https://doi.org/10.1101/433367

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