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.; Ng, M.C.Y.; Petty, L.E.; Kitajima, H.; Yu, G.Z.; Rüeger, 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.; Della Briotta Parolo, P.; Lin, K.; Bragg, F.; Preuss, M.H.; Takeuchi, F.; Nano, J.; Guo, X.; Lamri, A.; Nakatochi, M.; Scott, R.A.; Lee, 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.; 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.; Jensen, R.A.; Tajuddin, S.; Kabagambe, E.K.; An, P.; Xiang, A.H.; Choi, H.S.; Cade, B.E.; Tan, J.; 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.; Chuang, L.M.; Cushman, M.; Das, S.K.; de Silva, H.J.; Dedoussis, G.; Dimitrov, L.; Doumatey, A.P.; Du, S.; 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.; González-Villalpando, C.; González-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.; 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.; Jonas, J.B.; Jørgensen, M.E.; Jørgensen, 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.; Läll, K.; Lange, L.A.; Lee, M.S.; Lee, N.R.; Leong, A.; Li, L.; Li, Y.; Li-Gao, R.; Ligthart, S.; Lindgren, C.M.; Linneberg, A.; Liu, C.T.; Liu, J.; Locke, A.E.; Louie, T.; Luan, J.; 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.; Schönherr, S.; Schurmann, C.; Shahriar, M.; Shi, J.; Shin, D.M.; Shriner, D.; Smith, J.A.; So, W.Y.; Stančáková, 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.; van Dam, R.M.; van Klinken, J.B.; Varma, R.; Vujkovic, M.; Wacher-Rodarte, N.; Wheeler, E.; Whitsel, E.A.; Wickremasinghe, A.R.; van Dijk, K.W.; Witte, D.R.; Yajnik, C.S.; Yamamoto, K.; Yamauchi, T.; Yengo, L.; Yoon, K.; Yu, C.; 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.; 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.; Paré, G.; Sale, M.M.; Ahsan, H.; Motala, A.A.; Shu, X.O.; Park, K.S.; Jukema, J.W.; Cruz, M.; McKean-Cowdin, R.; Grallert, H.; Cheng, C.Y.; Bottinger, E.P.; Dehghan, A.; Tai, E.S.; Dupuis, J.; Kato, N.; Laakso, M.; Köttgen, A.; Koh, W.P.; Palmer, C.N A.; Liu, S.; Abecasis, G.; Kooner, J.S.; Loos, R.J.F.; North, K.E.; Haiman, C.A.; Florez, J.C.; Saleheen, D.; Hansen, T.; Pedersen, O.; Mägi, R.; Langenberg, C.; Wareham, N.J.; Maeda, S.; Kadowaki, T.; Lee, J.; Millwood, I.Y.; Walters, R.G.; Stefansson, K.; Myers, S.R.; Ferrer, J.; Gaulton, K.J.; Meigs, J.B.; Mohlke, K.L.; Gloyn, A.L.; Bowden, D.W.; Below, J.E.; Chambers, J.C.; Sim, X.; Boehnke, M.; Rotter, J.I.; McCarthy, M.I.; Morris, A.P.

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

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Item Type:	Article
Title:	Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
Creators:	Mahajan, A., Spracklen, C.N., Zhang, W., Ng, M.C.Y., Petty, L.E., Kitajima, H., Yu, G.Z., Rüeger, 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., Della Briotta Parolo, P., Lin, K., Bragg, F., Preuss, M.H., Takeuchi, F., Nano, J., Guo, X., Lamri, A., Nakatochi, M., Scott, R.A., Lee, 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., 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., Jensen, R.A., Tajuddin, S., Kabagambe, E.K., An, P., Xiang, A.H., Choi, H.S., Cade, B.E., Tan, J., 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., Chuang, L.M., Cushman, M., Das, S.K., de Silva, H.J., Dedoussis, G., Dimitrov, L., Doumatey, A.P., Du, S., 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., González-Villalpando, C., González-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., 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., Jonas, J.B., Jørgensen, M.E., Jørgensen, 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., Läll, K., Lange, L.A., Lee, M.S., Lee, N.R., Leong, A., Li, L., Li, Y., Li-Gao, R., Ligthart, S., Lindgren, C.M., Linneberg, A., Liu, C.T., Liu, J., Locke, A.E., Louie, T., Luan, J., 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. ORCID: https://orcid.org/0000-0001-5308-7785, Sandow, K., Sattar, N., Schönherr, S., Schurmann, C., Shahriar, M., Shi, J., Shin, D.M., Shriner, D., Smith, J.A., So, W.Y., Stančáková, 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., van Dam, R.M., van Klinken, J.B., Varma, R., Vujkovic, M., Wacher-Rodarte, N., Wheeler, E., Whitsel, E.A., Wickremasinghe, A.R., van Dijk, K.W., Witte, D.R., Yajnik, C.S., Yamamoto, K., Yamauchi, T., Yengo, L., Yoon, K., Yu, C., 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., 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., Paré, G., Sale, M.M., Ahsan, H., Motala, A.A., Shu, X.O., Park, K.S., Jukema, J.W., Cruz, M., McKean-Cowdin, R., Grallert, H., Cheng, C.Y., Bottinger, E.P., Dehghan, A., Tai, E.S., Dupuis, J., Kato, N., Laakso, M., Köttgen, A., Koh, W.P., Palmer, C.N A., Liu, S., Abecasis, G., Kooner, J.S., Loos, R.J.F., North, K.E., Haiman, C.A., Florez, J.C., Saleheen, D., Hansen, T., Pedersen, O., Mägi, R., Langenberg, C., Wareham, N.J., Maeda, S., Kadowaki, T., Lee, J., Millwood, I.Y., Walters, R.G., Stefansson, K., Myers, S.R., Ferrer, J., Gaulton, K.J., Meigs, J.B., Mohlke, K.L., Gloyn, A.L., Bowden, D.W., Below, J.E., Chambers, J.C., Sim, X., Boehnke, M., Rotter, J.I., McCarthy, M.I. and Morris, A.P.
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.
Keywords:	Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Risk Factors, Single Nucleotide Polymorphism, Type 2 Diabetes Mellitus
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	54
Number:	5
Page Range:	560-572
Date:	May 2022
Official Publication:	https://doi.org/10.1038/s41588-022-01058-3
PubMed:	View item in PubMed

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