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

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-an...

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Veröffentlicht in:	Nature genetics Jg. 54; H. 5; S. 560 - 572
Hauptverfasser:	Kitajima, Hidetoshi, Kim, Young Jin, Horikoshi, Momoko, Moon, Sanghoon, Robertson, Neil R., Nano, Jana, Lamri, Amel, Nakatochi, Masahiro, Graff, Mariaelisa, Yao, Jie, Bielak, Lawrence F., Hai, Yang, Schmidt, Ellen M., Nousome, Darryl, Trompet, Stella, Ahmad, Meraj, Noordam, Raymond, Lim, Victor J. Y., Joo, Yoonjung Yoonie, Prins, Bram Peter, Chen, Guanjie, Jensen, Richard A., Kabagambe, Edmond K., Xiang, Anny H., Flanagan, Jack, Adair, Linda S., Akiyama, Masato, Bertoni, Alain, Chee, Miao-Li, Chen, Shyh-Huei, Chen, Yuan-Tsong, Das, Swapan K., de Silva, H. Janaka, Eckardt, Kai-Uwe, Evans, Daniel S., Evans, Michele K., Franco, Oscar H., Fuchsberger, Christian, Genter, Pauline, Goodarzi, Mark O., Gordon-Larsen, Penny, Gorkin, David, Guo, Yu, Howard, Annie-Green, Hung, Yi-Jen, Hwang, Mi Yeong, Ingelsson, Martin, Jonas, Jost B., Jørgensen, Torben, Kamatani, Yoichiro, Kasturiratne, Anuradhani, Katsuya, Tomohiro, Keaton, Jacob M., Kho, Abel N., Khor, Chiea-Chuen, Läll, Kristi, Li-Gao, Ruifang, Liu, Jianjun, Luan, Jian’an, Luo, Xi, Lyssenko, Valeriya, Metspalu, Andres, Morris, Andrew D., Nalls, Michael A., Ntalla, Ioanna, Sattar, Naveed, Shi, Jinxiu, Shriner, Daniel, Stilp, Adrienne M., Takahashi, Atsushi, Taylor, Kent D., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Varma, Rohit, Yamamoto, Ken, Yoon, Kyungheon, Yusuf, Salim, Zheng, Wei, Cho, Yoon Shin, Lind, Lars, Province, Michael A., Zonderman, Alan B., Becker, Diane M., Yokota, Mitsuhiro, Chen, Yii-Der Ida, Ma, Ronald C. W., Chandak, Giriraj R., Sale, Michèle M., Shu, Xiao-Ou, Jukema, J. Wouter, McKean-Cowdin, Roberta, Kooner, Jaspal S., North, Kari E., Florez, Jose C., Maeda, Shiro, Stefansson, Kari, Mohlke, Karen L., Gloyn, Anna L., Below, Jennifer E., Rotter, Jerome I.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.05.2022 Nature Publishing Group
Schlagworte:	631/208/205/2138 692/699/2743/137/773 Agriculture Animal Genetics and Genomics Basic Medicine Biomedical and Life Sciences Biomedicine Cancer Research Conditional probability Consortia Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - epidemiology Ethnic factors Ethnicity Gene Function Gene mapping Genetic Predisposition to Disease Genome-wide association studies Genome-Wide Association Study Genomes Global health Health risk assessment Hispanic people Human Genetics Humans Life Sciences Localization Mapping Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Meta-analysis Molecular modelling Polymorphism, Single Nucleotide - genetics Population Population studies Populations Public health Risk Factors Translation
ISSN:	1061-4036, 1546-1718, 1546-1718
Online-Zugang:	Volltext
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Zusammenfassung:	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. 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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work. These authors supervised this work. AUTHOR CONTRIBUTIONS DIAMANTE Consortium co-ordination: A. Mahajan, M.I.M., A.P.M. Manuscript preparation: A. Mahajan, C.N.S., W. Zhang, M.C.Y.N., L.E.P., H.K., G.Z.Y., S. Rüeger, L.S., A.L.G., M.B., J.I.R., M.I.M., A.P.M. Co-ordination of ancestry-specific GWAS collections: A. Mahajan, C.N.S., W. Zhang, M.C.Y.N., L.E.P., D.W.B., J.E.B., J.C.C., X.S., M.B. Central analysis group: A. Mahajan, C.N.S., W. Zhang, M.C.Y.N., L.E.P., H.K., Y.J.K., M. Horikoshi, J.M.M., D.T., S. Moon, S.-H.K., N.R.R., N.W.R., M. Loh, B.-J.K., J. Flanagan, J.B.M., K.L.M., J.E.B., J.C.C., X.S., M.B., J.I.R., M.I.M., A.P.M. PROX1 functional analyses: G.Z.Y., F.A., J.M.T., A.L.G. GRS analyses in FinnGen: S. Rüeger, P.d.B.P. Selection analyses: L.S., S.R.M. Single cell chromatin accessibility data: J. Chiou, D.G., S.P., M. Sander, K.J.G. Islet promoter HiC data generation: I.M.-E., J. Ferrer. Study-level primary analyses: A. Mahajan, C.N.S., W. Zhang, M.C.Y.N., L.E.P., Y.J.K., M. Horikoshi, J.M.M., D.T., S. Moon, S.-H.K., K. Lin, F.B., M.H.P., F.T., J.N., X.G., A. Lamri, M.N., R.A.S., J.-J.L., A.H.-G., M. Graff, J.-F.C., E.J.P., J.Y., L.F.B., Y.T., Y.H., V.S., J.P.C., M.K., N.G., E.M.S., I.P., T.S., M.W., C. Sarnowski, C.G., D.N., S. Trompet, J. Long, M. Sun, L.T., W.-M.C., M. Ahmad, R.N., V.J.Y.L., C.H.T.T., Y.Y.J., C.-H.C., L.M.R., C. Lecoeur, B.P.P., A.N., L.R.Y., G.C., R.A.J., S. Tajuddin, E.K.K., P.A., A.H.X., H.S.C., B.E.C., J.Tan, X.S., A.P.M. Study-level phenotyping, genotyping and additional analyses: L.S.A., A.A., C.A.A.-S., M. Akiyama, S.S.A., A.B., Z.B., J.B.-J., I.B., J.A.B., C.M.B., T.B., M. Canouil, J.C.N.C, L.-C.C., M.L.C., J. Chen, S.-H.C., Y.-T.C., Z.C., C.C., L.-M.C., M. Cushman, S.K.D., H.J.d.S., G.D., L.D., A.P.D., S.D., Q.D., K.-U.E., L.S.E., D.S.E., M.K.E., K.F., J.S.F., I.F., M.F., O.H.F., T.M.F., B.I.F., C.F., P.G., H.C.G., V.G., C.G.-V., M.E.G.-V., M.O.G., P.G.-L., M. Gross, Y.G., S. Hackinger, S. Han, A.T.H., C.H., A.-G.H., W. Hsueh, M. Huang, W. Huang, Y.-J.H., M.Y.H., C.-M.H., S.I., M.A.I., M. Ingelsson, M.T.I., M. Isono, H.-M.J., F.J., G.J., J.B.J., M.E.J., T.J., Y.K., F.R.K., A. Kasturiratne, T. Katsuya, V.K., T. Kawaguchi, J.M.K., A.N.K., C.-C.K., M.G.K., K.K., J. Kriebel, F.K., J. Kuusisto, K. Läll, L.A.L., M.-S.L., N.R.L., A. Leong, L. Li, Y. Li, R.L.-G., S. Ligthart, C.M.L., A. Linneberg, C.-T.L., J. Liu, A.E.L., T.L., J. Luan, A.O.L., X.L., J. Lv, V.L., V.M., K.R.M., T.M., A. Metspalu, A.D.M., G.N.N., J.L.N., M.A.N., U.N., S.S.N., I.N., Y.O., L.O., S.R.P., M.A. Pereira, A.P., F.J.P., B.P., G. Prasad, L.J.R.-T., A.P.R, M.R., R.R., K.R., C. Sabanayagam, K. Sandow, N.S., S.S., C. Schurmann, M. Shahriar, J.S., D.M.S., D. Shriner, J.A.S., W.Y.S., A.S., A.M.S., K. Strauch, K. Suzuki, A.T., K.D.T., B. Thorand, G.T., U.T., B. Tomlinson, F.-J.T., J. Tuomilehto, T.T.-L., M.S.U., A.V.-S., R.M.v.D., J.B.v.K., R.V., M.V., N.W.-R., E.W., E.A.W., A.R.W., K.W.v.D., D.R.W., Y.-B.X., C.S.Y., K. Yamamoto, T.Y., L.Y., K. Yoon, C.Y., J.-M.Y., S.Y., L.Z., W. Zheng. Study-level principal investigator: L.J.R., M. Igase, E. Ipp, S. Redline, Y.S.C., L. Lind, M.A. Province, C.L.H., P.A.P., E. Ingelsson, A.B.Z., B.M.P., Y.-X.W., C.N.R., D.M.B., F.M., Y. Liu, E.Z., M.Y., S.S.R., C.K., J.S.P., J.C.E., Y.-D.I.C., P.F., J.G.W., W.H.H.S., S.L.R.K., J.-Y.W., M.G.H., R.C.W.M., T.-Y.W., L.G., D.O.M.-K., G.R.C., F.S.C., D.B., G. Pare, M.M.S., H.A., A.A.M., X.-O.S., K.-S.P., J.W.J., M. Cruz, R.M.-C., H.G., C.-Y.C., E.P.B., A.D., E.-S.T., J.D., N.K., M. Laakso, A. Köttgen, W.-P.K., C.N.A.P., S. Liu, G.A., J.S.K., R.J.F.L., K.E.N., C.A.H., J.C.F., D. Saleheen, T.H., O.P., R.M., C. Langenberg, N.J.W., S. Maeda, T. Kadowaki, J. Lee, I.Y.M., R.G.W., K. Stefansson, J.B.M., K.L.M., D.W.B., J.C.C., M.B., J.I.R., M.I.M., A.P.M.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-022-01058-3