Olga Giannakopoulou1, Kuang Lin2, Xiangrui Meng1, Mei-Hsin Su3, Po-Hsiu Kuo3,4, Roseann E Peterson5, Swapnil Awasthi6, Arden Moscati7, Jonathan R I Coleman8,9, Nick Bass1, Iona Y Millwood2,10, Yiping Chen2,10, Zhengming Chen2,10, Hsi-Chung Chen4, Mong-Liang Lu11,12, Ming-Chyi Huang12,13, Chun-Hsin Chen11,12, Eli A Stahl14, Ruth J F Loos7,15, Niamh Mullins14, Robert J Ursano16, Ronald C Kessler17, Murray B Stein18, Srijan Sen19, Laura J Scott20, Margit Burmeister21, Yu Fang22, Jess Tyrrell23, Yunxuan Jiang24, Chao Tian24, Andrew M McIntosh25, Stephan Ripke6,26,27, Erin C Dunn17,27,28, Kenneth S Kendler5, Robin G Walters2,10, Cathryn M Lewis8,9, Karoline Kuchenbaecker1,29. 1. Division of Psychiatry, University College of London, London, United Kingdom. 2. Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. 3. Institute of Epidemiology and Preventive Medicine, National Taiwan University College of Public Health, Taipei, Taiwan. 4. Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan. 5. Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia. 6. Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany. 7. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 8. Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom. 9. National Institute for Health Research Maudsley Biomedical Research Centre, King's College London, London, United Kingdom. 10. MRC Population Health Research Unit, University of Oxford, Oxford, United Kingdom. 11. Department of Psychiatry, Wan-Fang Hospital, Taipei, Taiwan. 12. School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 13. Department of Psychiatry, Taipei City Psychiatric Center, Taipei, Taiwan. 14. The Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York. 15. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 16. Uniformed Services University of the Health Sciences, Bethesda, Maryland. 17. Harvard Medical School, Boston, Massachusetts. 18. University of California, San Diego, La Jolla, California. 19. Michigan Neuroscience Institute, Department of Psychiatry, University of Michigan, Ann Arbor, Michigan. 20. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan. 21. Molecular & Behavioral Neuroscience Institute, Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan. 22. Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan. 23. University of Exeter Medical School, University of Exeter, The RILD Building, RD&E Hospital, Exeter, United Kingdom. 24. 23andme, Inc, Sunnyvale, California. 25. Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom. 26. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts. 27. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 28. Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts. 29. UCL Genetics Institute, University College of London, London, United Kingdom.
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.
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.