Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

David M Howard; Mark J Adams; Toni-Kim Clarke; Jonathan D Hafferty; Jude Gibson; Masoud Shirali; Jonathan R I Coleman; Saskia P Hagenaars; 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; Klaus Berger; Henning Teismann; Rajesh Rawal; Volker Arolt; Bernhard T Baune; Udo Dannlowski; Katharina Domschke; Chao Tian; David A Hinds; Maciej Trzaskowski; Enda M. Byrne; Stephan Ripke; Daniel J Smith; Patrick F Sullivan; Naomi R Wray; Gerome Breen; Cathryn M Lewis; Andrew M McIntosh; 23andMe Research Team

doi:10.1038/s41593-018-0326-7

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

David M Howard, Mark J Adams, Toni-Kim Clarke, Jonathan D Hafferty, Jude Gibson, Masoud Shirali, Jonathan R I Coleman, Saskia P Hagenaars, 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 HemaniKlaus Berger, Henning Teismann, Rajesh Rawal, Volker Arolt, Bernhard T Baune, Udo Dannlowski, Katharina Domschke, Chao Tian, David A Hinds, Maciej Trzaskowski, Enda M. Byrne, Stephan Ripke, Daniel J Smith, Patrick F Sullivan, Naomi R Wray, Gerome Breen, Cathryn M Lewis, Andrew M McIntosh, 23andMe Research Team

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1434 Citations (Scopus)

Abstract

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed 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 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

Original language	English
Journal	Nature Neuroscience
Volume	22
Issue	3
Pages (from-to)	343-352
Number of pages	10
ISSN	1097-6256
DOIs	https://doi.org/10.1038/s41593-018-0326-7
Publication status	Published - Mar 2019

Keywords

Cohort Studies
Depression/genetics
Depressive Disorder, Major/genetics
Female
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Male
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Prefrontal Cortex/metabolism
VRK2 RS2312147
PARTITIONING HERITABILITY
SCHIZOPHRENIA
DISORDERS
LOCI
MAJOR DEPRESSION
CIGARETTE-SMOKING
GENETICS
LD SCORE REGRESSION
ASSOCIATION

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10.1038/s41593-018-0326-7

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522363/pdf/emss-80873.pdf

Cite this

Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., Coleman, J. R. I., Hagenaars, S. P., Ward, J., Wigmore, E. M., Alloza, C., Shen, X., Barbu, M. C., Xu, E. Y., Whalley, H. C., Marioni, R. E., Porteous, D. J., Davies, G., Deary, I. J., ... 23andMe Research Team (2019). Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nature Neuroscience, 22(3), 343-352. https://doi.org/10.1038/s41593-018-0326-7

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title = "Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions",

abstract = "Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed 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 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.",

keywords = "Cohort Studies, Depression/genetics, Depressive Disorder, Major/genetics, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Prefrontal Cortex/metabolism, VRK2 RS2312147, PARTITIONING HERITABILITY, SCHIZOPHRENIA, DISORDERS, LOCI, MAJOR DEPRESSION, CIGARETTE-SMOKING, GENETICS, LD SCORE REGRESSION, ASSOCIATION",

author = "Howard, {David M} and Adams, {Mark J} and Toni-Kim Clarke and Hafferty, {Jonathan D} and Jude Gibson and Masoud Shirali and Coleman, {Jonathan R I} and Hagenaars, {Saskia P} and Joey Ward and Wigmore, {Eleanor M} and Clara Alloza and Xueyi Shen and Barbu, {Miruna C} and Xu, {Eileen Y} and Whalley, {Heather C} and Marioni, {Riccardo E} and Porteous, {David J} and Gail Davies and Deary, {Ian J} and Gibran Hemani and Klaus Berger and Henning Teismann and Rajesh Rawal and Volker Arolt and Baune, {Bernhard T} and Udo Dannlowski and Katharina Domschke and Chao Tian and Hinds, {David A} and Maciej Trzaskowski and Byrne, {Enda M.} and Stephan Ripke and Smith, {Daniel J} and Sullivan, {Patrick F} and Wray, {Naomi R} and Gerome Breen and Lewis, {Cathryn M} and McIntosh, {Andrew M} and {23andMe Research Team} and Manuel Mattheisen and Esben Agerbo and Buttensch{\o}n, {Henriette N{\o}rm{\o}lle} and Christensen, {Jane Hvarregaard} and Jakob Grove and Pedersen, {Carsten B{\o}cker} and Pedersen, {Marianne Gi{\o}rtz} and Per Qvist and Ole Mors and Mortensen, {Preben Bo} and Anders B{\o}rglum",

year = "2019",

month = mar,

doi = "10.1038/s41593-018-0326-7",

language = "English",

volume = "22",

pages = "343--352",

journal = "Nature Neuroscience",

issn = "1097-6256",

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Howard, DM, Adams, MJ, Clarke, T-K, Hafferty, JD, Gibson, J, Shirali, M, Coleman, JRI, Hagenaars, SP, Ward, J, Wigmore, EM, Alloza, C, Shen, X, Barbu, MC, Xu, EY, Whalley, HC, Marioni, RE, Porteous, DJ, Davies, G, Deary, IJ, Hemani, G, Berger, K, Teismann, H, Rawal, R, Arolt, V, Baune, BT, Dannlowski, U, Domschke, K, Tian, C, Hinds, DA, Trzaskowski, M, Byrne, EM, Ripke, S, Smith, DJ, Sullivan, PF, Wray, NR, Breen, G, Lewis, CM, McIntosh, AM & 23andMe Research Team 2019, 'Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions', Nature Neuroscience, vol. 22, no. 3, pp. 343-352. https://doi.org/10.1038/s41593-018-0326-7

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. / Howard, David M; Adams, Mark J; Clarke, Toni-Kim et al.
In: Nature Neuroscience, Vol. 22, No. 3, 03.2019, p. 343-352.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

AU - Howard, David M

AU - Adams, Mark J

AU - Clarke, Toni-Kim

AU - Hafferty, Jonathan D

AU - Gibson, Jude

AU - Shirali, Masoud

AU - Coleman, Jonathan R I

AU - Hagenaars, Saskia P

AU - Ward, Joey

AU - Wigmore, Eleanor M

AU - Alloza, Clara

AU - Shen, Xueyi

AU - Barbu, Miruna C

AU - Xu, Eileen Y

AU - Whalley, Heather C

AU - Marioni, Riccardo E

AU - Porteous, David J

AU - Davies, Gail

AU - Deary, Ian J

AU - Hemani, Gibran

AU - Berger, Klaus

AU - Teismann, Henning

AU - Rawal, Rajesh

AU - Arolt, Volker

AU - Baune, Bernhard T

AU - Dannlowski, Udo

AU - Domschke, Katharina

AU - Tian, Chao

AU - Hinds, David A

AU - Trzaskowski, Maciej

AU - Byrne, Enda M.

AU - Ripke, Stephan

AU - Smith, Daniel J

AU - Sullivan, Patrick F

AU - Wray, Naomi R

AU - Breen, Gerome

AU - Lewis, Cathryn M

AU - McIntosh, Andrew M

AU - 23andMe Research Team

AU - Mattheisen, Manuel

AU - Agerbo, Esben

AU - Buttenschøn, Henriette Nørmølle

AU - Christensen, Jane Hvarregaard

AU - Grove, Jakob

AU - Pedersen, Carsten Bøcker

AU - Pedersen, Marianne Giørtz

AU - Qvist, Per

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Børglum, Anders

PY - 2019/3

Y1 - 2019/3

N2 - Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed 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 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

AB - Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed 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 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

KW - Cohort Studies

KW - Depression/genetics

KW - Depressive Disorder, Major/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide

KW - Prefrontal Cortex/metabolism

KW - VRK2 RS2312147

KW - PARTITIONING HERITABILITY

KW - SCHIZOPHRENIA

KW - DISORDERS

KW - LOCI

KW - MAJOR DEPRESSION

KW - CIGARETTE-SMOKING

KW - GENETICS

KW - LD SCORE REGRESSION

KW - ASSOCIATION

U2 - 10.1038/s41593-018-0326-7

DO - 10.1038/s41593-018-0326-7

M3 - Journal article

C2 - 30718901

SN - 1097-6256

VL - 22

SP - 343

EP - 352

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 3

ER -

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

Abstract

Keywords

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