Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways

David M. Howard; Mark J. Adams; Masoud Shirali; Toni-Kim Clarke; Riccardo E. Marioni; Gail Davies; Jonathan R. I. Coleman; Clara Alloza; Xueyi Shen; Miruna C. Barbu; Eleanor M. Wigmore; Jude Gibson; 23andMe Research Team; Saskia P Hagenaars; Cathryn M. Lewis; Joey Ward; Daniel J Smith; Patrick F. Sullivan; Chris S. Haley; Gerome Breen; Ian J. Deary; Andrew M. McIntosh

doi:10.1038/s41467-018-03819-3

Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways

David M. Howard^*, Mark J. Adams, Masoud Shirali, Toni-Kim Clarke, Riccardo E. Marioni, Gail Davies, Jonathan R. I. Coleman, Clara Alloza, Xueyi Shen, Miruna C. Barbu, Eleanor M. Wigmore, Jude Gibson, 23andMe Research Team, Saskia P Hagenaars, Cathryn M. Lewis, Joey Ward, Daniel J Smith, Patrick F. Sullivan, Chris S. Haley, Gerome BreenIan J. Deary, Andrew M. McIntosh

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10⁻⁸) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.

Original language	English
Article number	1470
Pages (from-to)	1-10
Number of pages	10
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03819-3
Publication status	Published - 16 Apr 2018

Keywords / Materials (for Non-textual outputs)

Biological Specimen Banks
Biomarkers/metabolism
Cohort Studies
Depression/genetics
Depressive Disorder, Major/genetics
Gene Expression Regulation
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
International Classification of Diseases
Linkage Disequilibrium
Mechanotransduction, Cellular/genetics
Nerve Tissue Proteins/genetics
Phenotype
Synapses/genetics
Synaptic Transmission/genetics
United Kingdom

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Howard, D. M., Adams, M. J., Shirali, M., Clarke, T.-K., Marioni, R. E., Davies, G., Coleman, J. R. I., Alloza, C., Shen, X., Barbu, M. C., Wigmore, E. M., Gibson, J., 23andMe Research Team, Hagenaars, S. P., Lewis, C. M., Ward, J., Smith, D. J., Sullivan, P. F., Haley, C. S., ... McIntosh, A. M. (2018). Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nature Communications, 9(1), 1-10. Article 1470. https://doi.org/10.1038/s41467-018-03819-3

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title = "Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways",

abstract = "Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10−8) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.",

keywords = "Biological Specimen Banks, Biomarkers/metabolism, Cohort Studies, Depression/genetics, Depressive Disorder, Major/genetics, Gene Expression Regulation, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, International Classification of Diseases, Linkage Disequilibrium, Mechanotransduction, Cellular/genetics, Nerve Tissue Proteins/genetics, Phenotype, Synapses/genetics, Synaptic Transmission/genetics, United Kingdom",

author = "Howard, \{David M.\} and Adams, \{Mark J.\} and Masoud Shirali and Toni-Kim Clarke and Marioni, \{Riccardo E.\} and Gail Davies and Coleman, \{Jonathan R. I.\} and Clara Alloza and Xueyi Shen and Barbu, \{Miruna C.\} and Wigmore, \{Eleanor M.\} and Jude Gibson and \{23andMe Research Team\} and Hagenaars, \{Saskia P\} and Lewis, \{Cathryn M.\} and Joey Ward and Smith, \{Daniel J\} and Sullivan, \{Patrick F.\} and Haley, \{Chris S.\} and Gerome Breen and Deary, \{Ian J.\} and McIntosh, \{Andrew M.\}",

year = "2018",

month = apr,

day = "16",

doi = "10.1038/s41467-018-03819-3",

language = "English",

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pages = "1--10",

journal = "Nature Communications",

issn = "2041-1723",

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Howard, DM, Adams, MJ, Shirali, M, Clarke, T-K, Marioni, RE , Davies, G, Coleman, JRI, Alloza, C, Shen, X, Barbu, MC, Wigmore, EM, Gibson, J, 23andMe Research Team, Hagenaars, SP, Lewis, CM, Ward, J, Smith, DJ, Sullivan, PF, Haley, CS, Breen, G, Deary, IJ & McIntosh, AM 2018, 'Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways', Nature Communications, vol. 9, no. 1, 1470, pp. 1-10. https://doi.org/10.1038/s41467-018-03819-3

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T1 - Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways

AU - Howard, David M.

AU - Adams, Mark J.

AU - Shirali, Masoud

AU - Clarke, Toni-Kim

AU - Marioni, Riccardo E.

AU - Davies, Gail

AU - Coleman, Jonathan R. I.

AU - Alloza, Clara

AU - Shen, Xueyi

AU - Barbu, Miruna C.

AU - Wigmore, Eleanor M.

AU - Gibson, Jude

AU - 23andMe Research Team

AU - Hagenaars, Saskia P

AU - Lewis, Cathryn M.

AU - Ward, Joey

AU - Smith, Daniel J

AU - Sullivan, Patrick F.

AU - Haley, Chris S.

AU - Breen, Gerome

AU - Deary, Ian J.

AU - McIntosh, Andrew M.

PY - 2018/4/16

Y1 - 2018/4/16

N2 - Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10−8) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.

AB - Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10−8) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.

KW - Biological Specimen Banks

KW - Biomarkers/metabolism

KW - Cohort Studies

KW - Depression/genetics

KW - Depressive Disorder, Major/genetics

KW - Gene Expression Regulation

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - International Classification of Diseases

KW - Linkage Disequilibrium

KW - Mechanotransduction, Cellular/genetics

KW - Nerve Tissue Proteins/genetics

KW - Phenotype

KW - Synapses/genetics

KW - Synaptic Transmission/genetics

KW - United Kingdom

UR - https://www.scopus.com/pages/publications/85045552142

U2 - 10.1038/s41467-018-03819-3

DO - 10.1038/s41467-018-03819-3

M3 - Article

C2 - 29662059

SN - 2041-1723

VL - 9

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1470

ER -

Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways

Abstract

Keywords / Materials (for Non-textual outputs)

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Stratifying Resilience and Depression Longitudinally

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.