Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

"table 1 genes associated with md gene a drug b fuma c magma j d hi-c magma d twas p novel e credible set f genes associated in twas and hi-c magma ndufaf3 metformin nadh no 1 00 0 004 3 80 x 10 -7 yes9 pbrm1 alprazolam durvalumab everolimus no 0 10 0 017 3 20 x 10 -7 yes - tbca - no 0 16 0 042 1 29 x 10 -6 yes - btn2a3p - no 1 00 6 07 x 10 - 8 2 33 x 10 -8 yes - znf204p - no 1 00 0 014 2 13 x 10 -15 no - hla-b thalidomide ticlopidine phenobarbital carbamazepine clozapine lamotrigine no 0 46 3 7 x 10 -4 1 13 x 10 -7 no - rabgap1 - no 1 00 0 001 1 91 x 10 -8 yes - golga1 - no 1 00 0 020 1 56 x 10 -7 yes - frat2 - no 0 78 0 017 9 39 x 10 -7 yes - ensg00000278376 - no 0 06 0 004 6 55 x 10 -7 - 62 trhde-as1 - no 0 14 0 048 6 92 x 10 -7 yes - insyn1-as1 - no 0 25 0 014 5 53 x 10 -8 yes25 genes associated across all four methods rere - yes3 48 x 10 -8 1 29 x 10 -9 7 35 x 10 -16 no 45 negr1 - yes2 31 x 10 -6 1 53 x 10 -7 1 30 x 10 -26 no - znf638 cytidine yes0 003 0 004 5 64 x 10 -7 no 61 rftn2 lipopolysaccharide yes0 003 4 28 x 10 -4 1 52 x 10 -7 no 204 znf445 - yes3 35 x 10 -4 0 001 1 52 x 10 -10 no 138 znf197 - yes2 35 x 10 -4 8 04 x 10 -5 4 61 x 10 -10 no 138 ccdc71 - yes5 56 x 10 -5 0 039 3 12 x 10 -12 yes9 ensg00000225399 - yes0 010 0 003 1 07 x 10 -8 - 9 rhoa simvastatin pravastatin atorvastatin magnesium ccg-1423 yes0 031 0 019 1 45 x 10 -7 no 9 cdh9 calcium yes0 003 0 002 2 17 x 10 -8 no 95 tmem161b crofelemer yes2 79 x 10 -5 6 2 x 10 -8 5 26 x 10 -9 no - pfdn1 - yes0 025 2 94 x 10 -4 5 60 x 10 -8 yes67 slc4a9 sodium bicarbonate yes0 029 0 002 2 25 x 10 -12 no 67 hars1 adenosine phosphate pyrophosphate phosphate histidine yes0 024 0 017 5 29 x 10 -8 yes141 hars2 adenosine phosphate pyrophosphate phosphate histidine yes0 019 0 044 2 32 x 10 -8 no 141 zmat2 - yes0 014 0 005 1 11 x 10 -9 no 141 pcdha1 calcium yes0 015 0 005 1 15 x 10 -8 no 141 pcdha2 calcium yes0 031 0 010 1 55 x 10 -8 no 141 pcdha3 calcium yes0 043 0 004 1 06 x 10 -8 no 141 tmem106b crofelemer yes2 79 x 10 -5 1 57 x 10 -8 4 87 x 10 -15 no 1 zdhhc21 coenzyme a palmityl-coa yes0 002 0 036 5 13 x 10 -7 no 42 sorcs3 - yes2 23 x 10 -13 1 28 x 10 -8 1 98 x 10 -10 no 16 mybpc3 - yes0 004 0 012 9 23 x 10 -10 no 48 slc39a13 zinc chloride zinc sulfate yes0 007 0 003 9 14 x 10 -7 yes48 ctnnd1 - yes0 002 0 010 1 84 x 10 -7 no 60 ankk1 methadone naltrexone fostamatinib yes0 011 2 44 x 10 -6 1 41 x 10 -11 no - drd2 cabergoline ropinirole sulpiride yes9 11 x 10 -10 7 81 x 10 -10 3 95 x 10 -8 no - mlec - yes0 013 1 32 x 10 -6 8 90 x 10 -7 yes - sppl3 - yes3 6 x 10 -7 1 47 x 10 -7 1 89 x 10 -12 no - lrfn5 - yes4 28 x 10 -9 2 7 x 10 -4 5 79 x 10 -15 no 10 arel1 - yes0 007 5 64 x 10 -5 7 24 x 10 -12 no 143 dlst lipoic acid succinyl-coa coenzyme a dihydrolipoamide (s)-succinyldihydrolipoamide yes2 2 x 10 -4 0 001 1 51 x 10 -9 no 143 mark3 fostamatinib alsterpaullone yes1 43 x 10 -4 2 34 x 10 -5 3 50 x 10 -9 no 11 klc1 fluorouracil irinotecan leucovorin yes4 91 x 10 -9 9 99 x 10 -8 1 26 x 10 -12 no 11 xrcc3 fluorouracil irinotecan leucovorin yes0 004 7 73 x 10 -6 3 49 x 10 -10 no 11 zfyve21 inositol 13-bisphosphate yes3 0 x 10 -5 1 21 x 10 -7 2 83 x 10 -13 yes11 celf4 iloperidone yes1 52 x 10 -8 3 59 x 10 -5 9 66 x 10 -9 no 8 rab27b guanosine-5?-diphosphate yes1 23 x 10 -6 0 042 5 61 x 10 -10 no - emilin3 - yes0 039 0 001 6 66 x 10 -8 no 64 chd6 phosphate atp adp yes0 001 0 001 1 76 x 10 -10 no 64 ep300 acetyl-coa tgf-? garcinol cyclic amp curcumin mocetinostat yes4 95 x 10 -4 1 87 x 10 -6 1 71 x 10 -9 no 16 rangap1 - yes1 82 x 10 -4 0 003 6 73 x 10 -9 no 16 zc3h7b - yes0 001 2 03 x 10 -6 1 37 x 10 -9 no 16 this table includes12 genes significantly associated in the twas and hi-c magma that is not in physical proximity to a gwas hit and 43 genes significantly associated across all four methods (twas fuma magma and hi-c magma) a ensembl ids are shown for genes without symbol names b drugs targeting the prioritized genes or genes of the same family from genecards drugbank and chembl c gene mapped by fuma positional mapping or eqtl mapping d bonferroni adjusted two-sided p value for magma or hi-c magma of z statistics ( p < 0 05 implies statistical significance) e novel report as compared with previous magma and twas on md f number of variants in the 99% credible set only available for mapped loci from multi-ancestry fine-mapping. custom analysis scripts are available at 10 5281/zenodo 8335659."

"custom analysis scripts are available at 10 5281/zenodo 8335659."

"Competing interests O.G. is now a full-time employee at Union Chimique Belge. A.I.C. is currently an employee of Regeneron Pharmaceuticals and may own stock or stock options. C.T. reported being an employee of and receiving stock options from 23andMe during the conduct of the study. Y.J. reported being an employee of 23andMe outside the submitted work. All other authors declare no competing interests."

"We are grateful to all the participants who took part in the studies and acknowledge the investigators involved in the participating studies. We thank all members of the UCL HumGen laboratory (https://www.uclhumgen.com/), who gave critical support and suggestions. We thank A. Henry, University College London, for discussions and suggestions in key analytic techniques. This work was conducted on the University College London Computer Science cluster; we thank the cluster team for the support provided. China Kadoorie Biobank’s most important acknowledgement is to the participants in the study. The investigators also acknowledge the invaluable contributions of the members of the survey teams in each of the ten regional centres, and of the project development and management teams based at Beijing, Oxford and the ten regional centres. China’s National Health Insurance provides electronic linkage to all hospital treatments. The Mexican Adolescent Mental Health Survey cohort thanks C. Benjet and E. Méndez for their contributions to the Mexican Adolescent Mental Health Survey cohort’s data acquisition and curation, respectively. Intern Health Study thanks the training physicians for taking part in the Intern Health Study. This project was funded by the National Institute of Mental Health (grant no. R01MH101459). MVP thanks the veterans who participate in the MVP. From the Yale Department of Psychiatry, Division of Human Genetics, we thank and acknowledge the efforts of A. M. Lacobelle, C. Robinson and C. Tyrell. Funding: this work was supported by funding from the Veterans Affairs Office of Research and Development MVP grant CX001849- 01 (MVP025) and VA Cooperative Studies Program CSP575B. D.F.L. was supported by an NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. The BioVU study used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies and federal grants. These include the National Institutes of Health (NIH)-funded Shared Instrumentation grant S10RR025141; and Clinical and Translational Science Awards grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962 and R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/. CONVERGE authors are part of the CONVERGE consortium (China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology) and gratefully acknowledge the support of all partners in hospitals across China. Special thanks to all the CONVERGE collaborators and patients who made this work possible. CONVERGE Consortium: N. Cai, T. B. Bigdeli, W. Kretzschmar, Y. Li, J. Liang, L. Song, J. Hu, Q. Li, W. Jin, Z. Hu, G. Wang, L. Wang, P. Qian, Y. Liu, T. Jiang, Y. Lu, X. Zhang, Y. Yin, Y. Li, X. Xu, J. Gao, M. Reimers, T. Webb, B. Riley, S. Bacanu, R.E. Peterson, Y. Chen, H. Zhong, Z. Liu, G. Wang, J. Sun, H. Sang, G. Jiang, X. Zhou, Y. Li, Y. Li, W. Zhang, X. Wang, X. Fang, R. Pan, G. Miao, Q. Zhang, J. Hu, F. Yu, B. Du, W. Sang, K. Li, G. Chen, M. Cai, L. Yang, D. Yang, B. Ha, X. Hong, H. Deng, G. Li, K. Li, Y. Song, S. Gao, J. Zhang, Z. Gan, H. Meng, J. Pan, C. Gao, K. Zhang, N. Sun, Y. Li, Q. Niu, Y. Zhang, T. Liu, C. Hu, Z. Zhang, L. Lv, J. Dong, X. Wang, M. Tao, X. Wang, J. Xia, H. Rong, Q. He, T. Liu, G. Huang, Q. Mei, Z. Shen, Y. Liu, J. Shen, T. Tian, X. Liu, W. Wu, D. Gu, G. Fu, J. Shi, Y. Chen, X. Gan, L. Liu, L. Wang, F. Yang, E. Cong, J. Marchini, H. Yang, J. Wang, S. Shi, R. Mott, Q. Xu, J. Wang, K. S. Kendler and J. Flint. The AGDS is indebted to all of the participants for giving their time to contribute to this study. We thank all the people who helped in the conception, implementation, media campaign and data cleaning. We thank R. Parker, S. Cross and L. Sullivan for their valuable work coordinating all the administrative and operational aspects of the AGDS project. The 23andMe Study thanks the research participants and employees of 23andMe for making this work possible. Genes and Health thanks Social Action for Health, Centre of the Cell, members of our Community Advisory Group, and staff who have recruited and collected data from volunteers. We thank the NIHR National Biosample Centre (UK Biocentre), the Social Genetic and Developmental Psychiatry Centre (King’s College London), Wellcome Sanger Institute and the Broad Institute for sample processing, genotyping, sequencing and variant annotation. We thank Barts Health NHS Trust, NHS Clinical Commissioning Groups (City and Hackney, Waltham Forest, Tower Hamlets, Newham, Redbridge, Havering, Barking and Dagenham), East London NHS Foundation Trust, Bradford Teaching Hospitals NHS Foundation Trust, Public Health England (especially D. Wyllie), Discovery Data Service/Endeavour Health Charitable Trust (especially D. Stables) for General Data Protection Regulation compliant data sharing backed by individual written informed consent. Most of all we thank all of the volunteers participating in Genes and Health. Supplementary Tables 17–21 contain the complete list of members of the PGC-MDD Working Group, the 23andMe Research Team, the Genes and Health Research Team, the China Kadoorie Biobank Collaborative Group and the BioBank Japan Project. This study is part of a project that has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 948561) and from Wellcome (212360/Z/18/Z). Computing was supported by the Biotechnology and Biological Sciences Research Council (BB/R01356X/1). D.K. is supported by the MSCA Individual Fellowship, European Commission (101028810). G.N. is supported by the Biotechnology and Biological Sciences Research Council, grant number BB/M009513/1. R.P. is supported by grants from the NIH (R33 DA047527; R21 DC018098) and One Mind Rising Star Award. G.A.P. is supported by the Yale Biological Sciences Training Program (T32 MH014276). P.-H.K. is supported by The Ministry of Science and Technology Project (MOST 108-2314-B-002-136-MY3), the National Health Research Institutes Project (NHRI-EX106-10627NI) and the National Taiwan University Career Development Project (109L7860). A.M.M. is supported by grants from the Wellcome Trust (226770/Z/22/Z, 223165/Z/21/Z, 220857/Z/20/Z and 216767/Z/19/Z), UK Research and Innovation (MR/S035818/1 and MR/W014386/1), the United States NIH (R01MH124873) and the European Union Horizon 2020 scheme (grant agreement 847776). M.J.A. is supported by grants from the Wellcome Trust (104036/Z/14/Z and 220857/Z/20/Z). The AGDS was primarily funded by the National Health and Medical Research Council (NHMRC) of Australia grant 1086683. This work was further supported by NHMRC grants 1145645, 1078901, 1113400 and 1087889 and NIMH. The QSkin study was funded by the NHMRC (grant numbers 1073898, 1058522 and 1123248). N.G.M. is supported through NHMRC investigator grant 1172990. W.E. is supported by National Institute of Drug Abuse grant R01DA009897. CONVERGE was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/ Z/07/Z and WT089269/Z/09/Z) and by NIH grant MH100549. K.S.K. was supported by NIMH R01MH125938 and R21MH126358. R.E.P. was supported by NIMH R01MH125938, R21MH126358 and The Brain & Behavior Research Foundation NARSAD grant 28632 P&S Fund. L.K.D. is supported by funding R01 MH118223. R.J.U., R.C.K. and M.B.S. are supported by the US Department of Defense. J.G. and the MVP study were supported by funding from the Veterans Affairs Office of Research and Development MVP grant CX001849-01 (MVP025) and VA Cooperative Studies Program CSP575B. S.S. is supported by R01MH101459. M.U., D.E.W., and A.E.A. are supported by 2R01MD011728. C.S.C.-F. is supported by Cohen Veteran Bioscience, Mexico’s National Institute of Psychiatry, Mexico’s National Council of Science and Technology. The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I/N01-HC-65233), University of Miami (HHSN268201300004I/N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I/N01-HC-65236 Northwestern University) and San Diego State University (HHSN268201300005I/N01-HC-65237). The following institutes/centers/offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution–Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). The Hispanic Community Health Study/Study of Latinos also received support from the National Institutes of Health Award (R01MH113930). B.S.M. and W.E. are supported by the NIDA. J.A.R. and G.U. are supported by NIDA, NIA, VA, University of Maryland, Maryland VA Healthcare System, Baltimore Research and Education Foundation. The China Kadoorie Biobank baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. Long-term follow-up was supported by the Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z and 088158/Z/09/Z), the National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504 and 2016YFC1303904) and the National Natural Science Foundation of China (91843302). DNA extraction and genotyping was funde"