Abstract
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10−9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
| Original language | English |
|---|---|
| Pages (from-to) | 560-572 |
| Number of pages | 13 |
| Journal | Nature Genetics |
| Volume | 54 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2022 |
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In: Nature Genetics, Vol. 54, No. 5, 01.05.2022, p. 560-572.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
AU - FinnGen
AU - eMERGE Consortium
AU - Mahajan, Anubha
AU - Spracklen, Cassandra N.
AU - Zhang, Weihua
AU - Ng, Maggie C.Y.
AU - Petty, Lauren E.
AU - Kitajima, Hidetoshi
AU - Yu, Grace Z.
AU - Rüeger, Sina
AU - Speidel, Leo
AU - Kim, Young Jin
AU - Horikoshi, Momoko
AU - Mercader, Josep M.
AU - Taliun, Daniel
AU - Moon, Sanghoon
AU - Kwak, Soo Heon
AU - Robertson, Neil R.
AU - Rayner, Nigel W.
AU - Loh, Marie
AU - Kim, Bong Jo
AU - Chiou, Joshua
AU - Miguel-Escalada, Irene
AU - della Briotta Parolo, Pietro
AU - Lin, Kuang
AU - Bragg, Fiona
AU - Preuss, Michael H.
AU - Takeuchi, Fumihiko
AU - Nano, Jana
AU - Guo, Xiuqing
AU - Lamri, Amel
AU - Nakatochi, Masahiro
AU - Scott, Robert A.
AU - Lee, Jung Jin
AU - Huerta-Chagoya, Alicia
AU - Graff, Mariaelisa
AU - Chai, Jin Fang
AU - Parra, Esteban J.
AU - Yao, Jie
AU - Bielak, Lawrence F.
AU - Tabara, Yasuharu
AU - Hai, Yang
AU - Steinthorsdottir, Valgerdur
AU - Cook, James P.
AU - Kals, Mart
AU - Grarup, Niels
AU - Schmidt, Ellen M.
AU - Pan, Ian
AU - Sofer, Tamar
AU - Wuttke, Matthias
AU - Sarnowski, Chloe
AU - Gieger, Christian
AU - Nousome, Darryl
AU - Trompet, Stella
AU - Long, Jirong
AU - Sun, Meng
AU - Tong, Lin
AU - Chen, Wei Min
AU - Ahmad, Meraj
AU - Noordam, Raymond
AU - Lim, Victor J.Y.
AU - Tam, Claudia H.T.
AU - Joo, Yoonjung Yoonie
AU - Chen, Chien Hsiun
AU - Raffield, Laura M.
AU - Lecoeur, Cécile
AU - Prins, Bram Peter
AU - Nicolas, Aude
AU - Yanek, Lisa R.
AU - Chen, Guanjie
AU - Jensen, Richard A.
AU - Tajuddin, Salman
AU - Kabagambe, Edmond K.
AU - An, Ping
AU - Xiang, Anny H.
AU - Choi, Hyeok Sun
AU - Cade, Brian E.
AU - Tan, Jingyi
AU - Flanagan, Jack
AU - Abaitua, Fernando
AU - Adair, Linda S.
AU - Adeyemo, Adebowale
AU - Aguilar-Salinas, Carlos A.
AU - Akiyama, Masato
AU - Anand, Sonia S.
AU - Bertoni, Alain
AU - Bian, Zheng
AU - Bork-Jensen, Jette
AU - Brandslund, Ivan
AU - Brody, Jennifer A.
AU - Brummett, Chad M.
AU - Buchanan, Thomas A.
AU - Canouil, Mickaël
AU - Chan, Juliana C.N.
AU - Chang, Li Ching
AU - Chee, Miao Li
AU - Chen, Ji
AU - Chen, Shyh Huei
AU - Chen, Yuan Tsong
AU - Chen, Zhengming
AU - Chuang, Lee Ming
AU - Cushman, Mary
AU - Das, Swapan K.
AU - de Silva, H. Janaka
AU - Dedoussis, George
AU - Dimitrov, Latchezar
AU - Doumatey, Ayo P.
AU - Du, Shufa
AU - Duan, Qing
AU - Eckardt, Kai Uwe
AU - Emery, Leslie S.
AU - Evans, Daniel S.
AU - Evans, Michele K.
AU - Fischer, Krista
AU - Floyd, James S.
AU - Ford, Ian
AU - Fornage, Myriam
AU - Franco, Oscar H.
AU - Frayling, Timothy M.
AU - Freedman, Barry I.
AU - Fuchsberger, Christian
AU - Genter, Pauline
AU - Gerstein, Hertzel C.
AU - Giedraitis, Vilmantas
AU - González-Villalpando, Clicerio
AU - González-Villalpando, Maria Elena
AU - Goodarzi, Mark O.
AU - Gordon-Larsen, Penny
AU - Gorkin, David
AU - Gross, Myron
AU - Guo, Yu
AU - Hackinger, Sophie
AU - Han, Sohee
AU - Hattersley, Andrew T.
AU - Herder, Christian
AU - Howard, Annie Green
AU - Hsueh, Willa
AU - Huang, Mengna
AU - Huang, Wei
AU - Hung, Yi Jen
AU - Hwang, Mi Yeong
AU - Hwu, Chii Min
AU - Ichihara, Sahoko
AU - Ikram, Mohammad Arfan
AU - Ingelsson, Martin
AU - Islam, Md Tariqul
AU - Isono, Masato
AU - Jang, Hye Mi
AU - Jasmine, Farzana
AU - Jiang, Guozhi
AU - Jonas, Jost B.
AU - Jørgensen, Marit E.
AU - Jørgensen, Torben
AU - Kamatani, Yoichiro
AU - Kandeel, Fouad R.
AU - Kasturiratne, Anuradhani
AU - Katsuya, Tomohiro
AU - Kaur, Varinderpal
AU - Kawaguchi, Takahisa
AU - Keaton, Jacob M.
AU - Kho, Abel N.
AU - Khor, Chiea Chuen
AU - Kibriya, Muhammad G.
AU - Kim, Duk Hwan
AU - Kohara, Katsuhiko
AU - Kriebel, Jennifer
AU - Kronenberg, Florian
AU - Kuusisto, Johanna
AU - Läll, Kristi
AU - Lange, Leslie A.
AU - Lee, Myung Shik
AU - Lee, Nanette R.
AU - Leong, Aaron
AU - Li, Liming
AU - Li, Yun
AU - Li-Gao, Ruifang
AU - Ligthart, Symen
AU - Lindgren, Cecilia M.
AU - Linneberg, Allan
AU - Liu, Ching Ti
AU - Liu, Jianjun
AU - Locke, Adam E.
AU - Louie, Tin
AU - Luan, Jian’an
AU - Luk, Andrea O.
AU - Luo, Xi
AU - Lv, Jun
AU - Lyssenko, Valeriya
AU - Mamakou, Vasiliki
AU - Mani, K. Radha
AU - Meitinger, Thomas
AU - Metspalu, Andres
AU - Morris, Andrew D.
AU - Nadkarni, Girish N.
AU - Nadler, Jerry L.
AU - Nalls, Michael A.
AU - Nayak, Uma
AU - Nongmaithem, Suraj S.
AU - Ntalla, Ioanna
AU - Okada, Yukinori
AU - Orozco, Lorena
AU - Province, Michael A.
N1 - Funding Information: A complete list of acknowledgements and funding appears in the . This research was funded in part by the Wellcome Trust (grant numbers 064890, 072960, 083948, 084723, 085475, 086113, 088158, 090367, 090532, 095101, 098017, 098051, 098381, 098395, 101033, 101630, 104085, 106130, 200186, 200837, 202922, 203141, 206194, 212259, 212284, 212946 and 220457). For the purpose of open access, the authors have applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission. Funding Information: A. Mahajan is now an employee of Genentech and a holder of Roche stock. R.A.S. is now an employee of GlaxoSmithKline. V.S. is an employee of deCODE Genetics–Amgen. L.S.E. is now an employee of Bristol Myers Squibb. J.S.F. has consulted for Shionogi. T.M.F. has consulted for Sanofi and Boerhinger Ingelheim and received funding from GSK. H.C.G. holds the McMaster–Sanofi Population Health Institute Chair in Diabetes Research and Care; reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi; reports honoraria for speaking from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Roche and Sanofi; and reports consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, Sanofi, Kowa and Hanmi. M. Ingelsson is a paid consultant for BioArctic. R.L.-G. is a part-time consultant for Metabolon. A.E.L. is now an employee of the Regeneron Genetics Center and holds shares in Regeneron Pharmaceuticals. M.A.N. currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23. S.R.P. has received grant funding from Bayer Pharmaceuticals, Philips Respironics and Respicardia. N.S. has consulted for or been on speaker bureaus for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Novartis, Novo Nordisk, Sanofi and Pfizer and has received grant funding from AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics. A.M.S. receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. G.T. is an employee of deCODE Genetics–Amgen. U.T. is an employee of deCODE Genetics–Amgen. E. Ingelsson is now an employee of GlaxoSmithKline. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. R.C.W.M. reports research funding from AstraZeneca, Bayer, Novo Nordisk, Pfizer, Tricida and Sanofi and has consulted for or received speakers fees from AstraZeneca, Bayer and Boehringer Ingelheim, all of which have been donated to the Chinese University of Hong Kong to support diabetes research. D.O.M.-K. is a part-time clinical research consultant for Metabolon. S. Liu reports consulting payments and honoraria or promises of the same for scientific presentations or reviews at numerous venues, including but not limited to Barilla, by-Health, Ausa Pharmed, the Fred Hutchinson Cancer Center, Harvard University, the University of Buffalo, Guangdong General Hospital and the Academy of Medical Sciences; is a consulting member for Novo Nordisk; is a member of the data safety and monitoring board for a trial of pulmonary hypertension in patients with diabetes at Massachusetts General Hospital; receives royalties from UpToDate; and receives an honorarium from the American Society for Nutrition for his duties as an associate editor. K. Stefansson is an employee of deCODE Genetics–Amgen. K.J.G. consults for Genentech and holds stock in Vertex Pharmaceuticals. A.L.G.’s spouse is an employee of Genentech and holds stock options in Roche. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk and Zoe Global; has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly and research funding from AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda; is now an employee of Genentech and a holder of Roche stock. The remaining authors declare no competing interests. The views expressed in this article are those of the authors and do not necessarily represent those of the NHS, the NIHR or the UK Department of Health; the National Heart, Lung, and Blood Institute, the National Institutes of Health or the US Department of Health and Human Services. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10−9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
AB - We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10−9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
UR - http://www.scopus.com/inward/record.url?scp=85130637871&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01058-3
DO - 10.1038/s41588-022-01058-3
M3 - Article
C2 - 35551307
AN - SCOPUS:85130637871
SN - 1061-4036
VL - 54
SP - 560
EP - 572
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -