Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Mahajan, A.; Spracklen, C.N.; Zhang, W.H.; Ng, M.C.Y.; Petty, L.E.; Kitajima, H.; ... ; Bharadwaj, D. (2022)

Article / Letter to editor

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 x 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.Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

• All authors: Mahajan, A.; Spracklen, C.N.; Zhang, W.H.; Ng, M.C.Y.; Petty, L.E.; Kitajima, H.; Yu, G.Z.; Rueger, S.; Speidel, L.; Kim, Y.J.; Horikoshi, M.; Mercader, J.M.; Taliun, D.; Moon, S.; Kwak, S.H.; Robertson, N.R.; Rayner, N.W.; Loh, M.; Kim, B.J.; Chiou, J.; Miguel-Escalada, I.; Parolo, P.D.; Lin, K.; Bragg, F.; Preuss, M.H.; Takeuchi, F.; Nano, J.; Guo, X.Q.; Lamri, A.; Nakatochi, M.; Scott, R.A.; Lee, J.J.; Huerta-Chagoya, A.; Graff, M.; Chai, J.F.; Parra, E.J.; Yao, J.; Bielak, L.F.; Tabara, Y.; Hai, Y.; Steinthorsdottir, V.; Cook, J.P.; Kals, M.; Grarup, N.; Schmidt, E.M.; Pan, I.; Sofer, T.; Wuttke, M.; Sarnowski, C.; Gieger, C.; Nousome, D.; Trompet, S.; Long, J.R.; Sun, M.; Tong, L.; Chen, W.M.; Ahmad, M.; Noordam, R.; Lim, V.J.Y.; Tam, C.H.T.; Joo, Y.Y.; Chen, C.H.; Raffield, L.M.; Lecoeur, C.; Prins, B.P.; Nicolas, A.; Yanek, L.R.; Chen, G.J.; Jensen, R.A.; Tajuddin, S.; Kabagambe, E.K.; An, P.; Xiang, A.H.; Choi, H.S.; Cade, B.E.; Tan, J.Y.; Flanagan, J.; Abaitua, F.; Adair, L.S.; Adeyemo, A.; Aguilar-Salinas, C.A.; Akiyama, M.; Anand, S.S.; Bertoni, A.; Bian, Z.; Bork-Jensen, J.; Brandslund, I.; Brody, J.A.; Brummett, C.M.; Buchanan, T.A.; Canouil, M.; Chan, J.C.N.; Chang, L.C.; Chee, M.L.; Chen, J.; Chen, S.H.; Chen, Y.T.; Chen, Z.M.; Chuang, L.M.; Cushman, M.; S.K. das; Silva, H.J. de; Dedoussis, G.; Dimitrov, L.; Doumatey, A.P.; S.F. du; Duan, Q.; Eckardt, K.U.; Emery, L.S.; Evans, D.S.; Evans, M.K.; Fischer, K.; Floyd, J.S.; Ford, I.; Fornage, M.; Franco, O.H.; Frayling, T.M.; Freedman, B.I.; Fuchsberger, C.; Genter, P.; Gerstein, H.C.; Giedraitis, V.; Gonzalez-Villalpando, C.; Gonzalez-Villalpando, M.E.; Goodarzi, M.O.; Gordon-Larsen, P.; Gorkin, D.; Gross, M.; Guo, Y.; Hackinger, S.; Han, S.; Hattersley, A.T.; Herder, C.; Howard, A.G.; Hsueh, W.; Huang, M.N.; Huang, W.; Hung, Y.J.; Hwang, M.Y.; Hwu, C.M.; Ichihara, S.; Ikram, M.A.; Ingelsson, M.; Islam, M.T.; Isono, M.; Jang, H.M.; Jasmine, F.; Jiang, G.Z.; Jonas, J.B.; Jorgensen, M.E.; Jorgensen, T.; Kamatani, Y.; Kandeel, F.R.; Kasturiratne, A.; Katsuya, T.; Kaur, V.; Kawaguchi, T.; Keaton, J.M.; Kho, A.N.; Khor, C.C.; Kibriya, M.G.; Kim, D.H.; Kohara, K.; Kriebel, J.; Kronenberg, F.; Kuusisto, J.; Lall, K.; Lange, L.A.; Lee, M.S.; Lee, N.R.; Leong, A.; Li, L.M.; Li, Y.; Li-Gao, R.F.; Ligthart, S.; Lindgren, C.M.; Linneberg, A.; Liu, C.T.; Liu, J.J.; Locke, A.E.; Louie, T.; Luan, J.A.; Luk, A.O.; Luo, X.; Lv, J.; Lyssenko, V.; Mamakou, V.; Mani, K.R.; Meitinger, T.; Metspalu, A.; Morris, A.D.; Nadkarni, G.N.; Nadler, J.L.; Nalls, M.A.; Nayak, U.; Nongmaithem, S.S.; Ntalla, I.; Okada, Y.; Orozco, L.; Patel, S.R.; Pereira, M.A.; Peters, A.; Pirie, F.J.; Porneala, B.; Prasad, G.; Preissl, S.; Rasmussen-Torvik, L.J.; Reiner, A.P.; Roden, M.; Rohde, R.; Roll, K.; Sabanayagam, C.; Sander, M.; Sandow, K.; Sattar, N.; Schonherr, S.; Schurmann, C.; Shahriar, M.; Shi, J.X.; Shin, D.M.; Shriner, D.; Smith, J.A.; So, W.Y.; Stancakova, A.; Stilp, A.M.; Strauch, K.; Suzuki, K.; Takahashi, A.; Taylor, K.D.; Thorand, B.; Thorleifsson, G.; Thorsteinsdottir, U.; Tomlinson, B.; Torres, J.M.; Tsai, F.J.; Tuomilehto, J.; Tusie-Luna, T.; Udler, M.S.; Valladares-Salgado, A.; Dam, R.M. van; Klinken, J.B. van; Varma, R.; Vujkovic, M.; Wacher-Rodarte, N.; Wheeler, E.; Whitsel, E.A.; Wickremasinghe, A.R.; Dijk, K.W. van; Witte, D.R.; Yajnik, C.S.; Yamamoto, K.; Yamauchi, T.; Yengo, L.; Yoon, K.; Yu, C.Q.; Yuan, J.M.; Yusuf, S.; Zhang, L.; Zheng, W.; Raffel, L.J.; Igase, M.; Ipp, E.; Redline, S.; Cho, Y.S.; Lind, L.; Province, M.A.; Hanis, C.L.; Peyser, P.A.; Ingelsson, E.; Zonderman, A.B.; Psaty, B.M.; Wang, Y.X.; Rotimi, C.N.; Becker, D.M.; Matsuda, F.; Liu, Y.M.; Zeggini, E.; Yokota, M.; Rich, S.S.; Kooperberg, C.; Pankow, J.S.; Engert, J.C.; Chen, Y.D.I.; Froguel, P.; Wilson, J.G.; Sheu, W.H.H.; Kardia, S.L.R.; Wu, J.Y.; Hayes, M.G.; Ma, R.C.W.; Wong, T.Y.; Groop, L.; Mook-Kanamori, D.O.; Chandak, G.R.; Collins, F.S.; Bharadwaj, D.
• Date: 2022-05-12
• Journal: Nature Genetics
• Volume: 54
• Issue: 5
• Pages: 560 - +
• DOI: doi:10.1038/s41588-022-01058-3