The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study

Olga Giannakopoulou, Kuang Lin, Cathryn M Lewis, Karoline Kuchenbaecker, 23andMe Research Team, Jouke Jan Hottenga, Rick Jansen, Hamdi Mbarek, Christel M. Middeldorp, Yuri Milaneschi, Michel Nivard, Wouter Peyrot, Danielle Posthuma, Gonneke Willemsen, Dorret Boomsma, Eco J.C. de Geus, Brenda WJH Penninx

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations.

Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression.

Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021.

Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts.

Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires.

Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent.

Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.

Original languageEnglish
Pages (from-to)1258-1269
Number of pages12
JournalJAMA Psychiatry
Volume78
Issue number11
DOIs
Publication statusPublished - 1 Nov 2021

Funding

Dr Giannakopoulou became a full-time employee of UCB ((Union Chimique Belge) while this manuscript was being resubmitted. Dr Peterson reported receiving grants from the National Institutes of Health (NIH) (K01MH113848) and the Brain & Behavior Research Foundation (NARSAD, 28632 P&S Fund) during the conduct of the study. Mr Moscati reported being a current employee of Regeneron Pharmaceuticals, but he was not when contributions to this work were made. Dr Stahl reported being an employee of Regeneron Pharmaceuticals outside the submitted work. Dr Kessler reported receiving personal fees from Datastat Inc and consultant and personal fees from RallyPoint Networks Inc, Sage Pharmaceuticals, and Takeda during the conduct of the study. Dr Stein reported receiving grants from the National Institute of Mental Health (NIMH) and the Department of Defense during the conduct of the study. Dr Jiang reported being an employee of 23andMe outside the submitted work. Dr Tian reported being an employee of and receiving stock options from 23andMe during the conduct of the study. Dr McIntosh reported receiving grants from The Sackler Trust, personal fees from Illumina, and personal fees from Janssen outside the submitted work. Dr Walters reported receiving grants from Wellcome Trust (UK), Medical Research Council (UK), and Kadoorie Charitable Foundation (Hong Kong) during the conduct of the study. Dr Lewis reported receiving grants from the National Institute of Health Research (UK) during the conduct of the study. No other disclosures were reported. is supported by The Andrea and Charles Bronfman Philanthropies. R.J.F.L. is supported by funds of the NIH (R01DK110113; R01DK107786; R01HL142302). Genotyping of BioMe was performed in collaboration with Regeneron Genetics Center, who had no input as to the design and conduct of the study, the interpretation of the data, and preparation, review, or decision to submit the manuscript for publication. Taiwan-MDD was supported by projects from the National Health Research Institutes (NHRI-EX107-10627NI), the Ministry of Science and Technology (MOST 105-2628-B-002-028-MY3, 108-2314-B-002-136-MY3), and the National Taiwan University Career Development Project (104R7883, 108L7860) to P-H.K. Army STARRS: This research was supported by grants awarded from the Department of the Army and funded under cooperative agreement with the US Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) [U01MH087981]. Subsequently, STARRS-LS was sponsored and funded by the Department of Defense (USUHS grant number HU0001-15-2-0004). The contents are solely the responsibility of the authors and do not necessarily represent the views of the Department of Health and Human Services, NIMH, the Veterans Administration, Department of the Army, or the Department of Defense. IHS was funded by the National Institute of Mental Health (grant no. R01MH101459). Funding/Support: This study is part of a project that has received funding from Wellcome (212360/ Z/18/Z) and from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant agreement No. 948561). Computing was supported by the BBSRC Biotechnology and Biological Sciences Research Council (BB/R01356X/1). Dr Lewis is supported by the MRC grant MR/N015746/1. Dr McIntosh is supported by the Wellcome Trust (104036/Z/14/Z, 216767/Z/19/Z), UKRI MRC (MC_PC_17209, MR/S035818/1). Dr Tyrrell is supported by an Academy of Medical Sciences (AMS) Springboard award, which is supported by the AMS, the Wellcome Trust, GCRF, the Government Department of Business, Energy and Industrial strategy, the British Heart Foundation and Diabetes UK [SBF004\1079]. Dr Dunn is supported in part by the National Institute of Mental Health of the National Institutes of Health under Award Number 1R01MH113930. This paper represents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. China Kadoorie Biobank (CKB): Baseline survey and first re-survey: Hong Kong Kadoorie Charitable Foundation; long-term follow-up: UK Wellcome Trust (202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/ 09/Z), National Natural Science Foundation of China (81390540, 81390541, 81390544), and National Key Research and Development Program of China (2016YFC 0900500, 0900501, 0900504, 1303904). DNA extraction and genotyping supported by GlaxoSmithKline and the UK Medical Research Council (MC-PC-13049, MC-PC-14135). The project was supported by British Heart Foundation, UK MRC and Cancer Research UK through core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University. CONVERGE was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/ Z/07/Z, WT089269/Z/09/Z) and by NIH grant MH100549. R.E.P. is supported by NIMH grant K01MH113848 and The Brain & Behavior Research Foundation NARSAD grant 28632 P&S Fund. BioMe

FundersFunder number
British Heart Foundation, UK MRC
Department of the Army
Hong Kong Kadoorie Charitable Foundation104085/Z/14/Z, 202922/Z/16/Z, 088158/Z/ 09/Z
UKRI MRCMR/S035818/1, MC_PC_17209
National Institutes of HealthR01HL142302, 1R01MH113930, R01DK110113, MH100549
U.S. Department of Defense
U.S. Department of Health and Human Services
National Institute of Mental HealthK01MH113848, U01MH087981
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK107786
Brain and Behavior Research Foundation28632
GlaxoSmithKline
Uniformed Services University of the Health SciencesHU0001-15-2-0004, R01MH101459
National Alliance for Research on Schizophrenia and Depression
Wellcome Trust104036/Z/14/Z, 216767/Z/19/Z, 212360/ Z/18/Z
Horizon 2020 Framework Programme948561
Sackler Trust
Global Challenges Research Fund
Medical Research CouncilMC-PC-14135, MR/N015746/1, MC-PC-13049
Biotechnology and Biological Sciences Research CouncilBB/R01356X/1
National Institute for Health Research
British Heart Foundation
Cancer Research UKWT090532/Z/09/Z, WT089269/Z/09/Z, WT083573/ Z/07/Z
Diabetes UKSBF004\1079
Academy of Medical Sciences
European Research Council
National Natural Science Foundation of China81390544, 81390540, 81390541
Ministry of Science and Technology, Taiwan108-2314-B-002-136-MY3, 105-2628-B-002-028-MY3
National Health Research InstitutesNHRI-EX107-10627NI
National Taiwan University108L7860, 104R7883
National Key Research and Development Program of China2016YFC 0900500, 0900501, 0900504, 1303904
Kadoorie Charitable Foundation

    Keywords

    • Adult
    • Asians/ethnology
    • Depression/ethnology
    • Depressive Disorder/ethnology
    • Far East/ethnology
    • Female
    • Genome-Wide Association Study
    • Humans
    • Male
    • Middle Aged
    • Whites/genetics

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