Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium None., Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium None., South Asian Type 2 Diabetes (SAT2D) Consortium None., Mexican American Type 2 Diabetes (MAT2D) Consortium None., Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium None., Mahajan A., Go MJ., Zhang W., Below JE., Gaulton KJ., Ferreira T., Horikoshi M., Johnson AD., Ng MCY., Prokopenko I., Saleheen D., Wang X., Zeggini E., Abecasis GR., Adair LS., Almgren P., Atalay M., Aung T., Baldassarre D., Balkau B., Bao Y., Barnett AH., Barroso I., Basit A., Been LF., Beilby J., Bell GI., Benediktsson R., Bergman RN., Boehm BO., Boerwinkle E., Bonnycastle LL., Burtt N., Cai Q., Campbell H., Carey J., Cauchi S., Caulfield M., Chan JCN., Chang L-C., Chang T-J., Chang Y-C., Charpentier G., Chen C-H., Chen H., Chen Y-T., Chia K-S., Chidambaram M., Chines PS., Cho NH., Cho YM., Chuang L-M., Collins FS., Cornelis MC., Couper DJ., Crenshaw AT., van Dam RM., Danesh J., Das D., de Faire U., Dedoussis G., Deloukas P., Dimas AS., Dina C., Doney AS., Donnelly PJ., Dorkhan M., van Duijn C., Dupuis J., Edkins S., Elliott P., Emilsson V., Erbel R., Eriksson JG., Escobedo J., Esko T., Eury E., Florez JC., Fontanillas P., Forouhi NG., Forsen T., Fox C., Fraser RM., Frayling TM., Froguel P., Frossard P., Gao Y., Gertow K., Gieger C., Gigante B., Grallert H., Grant GB., Grrop LC., Groves CJ., Grundberg E., Guiducci C., Hamsten A., Han B-G., Hara K., Hassanali N., Hattersley AT., Hayward C., Hedman AK., Herder C., Hofman A., Holmen OL., Hovingh K., Hreidarsson AB., Hu C., Hu FB., Hui J., Humphries SE., Hunt SE., Hunter DJ., Hveem K., Hydrie ZI., Ikegami H., Illig T., Ingelsson E., Islam M., Isomaa B., Jackson AU., Jafar T., James A., Jia W., Jöckel K-H., Jonsson A., Jowett JBM., Kadowaki T., Kang HM., Kanoni S., Kao WHL., Kathiresan S., Kato N., Katulanda P., Keinanen-Kiukaanniemi KM., Kelly AM., Khan H., Khaw K-T., Khor C-C., Kim H-L., Kim S., Kim YJ., Kinnunen L., Klopp N., Kong A., Korpi-Hyövälti E., Kowlessur S., Kraft P., Kravic J., Kristensen MM., Krithika S., Kumar A., Kumate J., Kuusisto J., Kwak SH., Laakso M., Lagou V., Lakka TA., Langenberg C., Langford C., Lawrence R., Leander K., Lee J-M., Lee NR., Li M., Li X., Li Y., Liang J., Liju S., Lim W-Y., Lind L., Lindgren CM., Lindholm E., Liu C-T., Liu JJ., Lobbens S., Long J., Loos RJF., Lu W., Luan J., Lyssenko V., Ma RCW., Maeda S., Mägi R., Männisto S., Matthews DR., Meigs JB., Melander O., Metspalu A., Meyer J., Mirza G., Mihailov E., Moebus S., Mohan V., Mohlke KL., Morris AD., Mühleisen TW., Müller-Nurasyid M., Musk B., Nakamura J., Nakashima E., Navarro P., Ng P-K., Nica AC., Nilsson PM., Njølstad I., Nöthen MM., Ohnaka K., Ong TH., Owen KR., Palmer CNA., Pankow JS., Park KS., Parkin M., Pechlivanis S., Pedersen NL., Peltonen L., Perry JRB., Peters A., Pinidiyapathirage JM., Platou CG., Potter S., Price JF., Qi L., Radha V., Rallidis L., Rasheed A., Rathman W., Rauramaa R., Raychaudhuri S., Rayner NW., Rees SD., Rehnberg E., Ripatti S., Robertson N., Roden M., Rossin EJ., Rudan I., Rybin D., Saaristo TE., Salomaa V., Saltevo J., Samuel M., Sanghera DK., Saramies J., Scott J., Scott LJ., Scott RA., Segrè AV., Sehmi J., Sennblad B., Shah N., Shah S., Shera AS., Shu XO., Shuldiner AR., Sigurđsson G., Sijbrands E., Silveira A., Sim X., Sivapalaratnam S., Small KS., So WY., Stančáková A., Stefansson K., Steinbach G., Steinthorsdottir V., Stirrups K., Strawbridge RJ., Stringham HM., Sun Q., Suo C., Syvänen A-C., Takayanagi R., Takeuchi F., Tay WT., Teslovich TM., Thorand B., Thorleifsson G., Thorsteinsdottir U., Tikkanen E., Trakalo J., Tremoli E., Trip MD., Tsai FJ., Tuomi T., Tuomilehto J., Uitterlinden AG., Valladares-Salgado A., Vedantam S., Veglia F., Voight BF., Wang C., Wareham NJ., Wennauer R., Wickremasinghe AR., Wilsgaard T., Wilson JF., Wiltshire S., Winckler W., Wong TY., Wood AR., Wu J-Y., Wu Y., Yamamoto K., Yamauchi T., Yang M., Yengo L., Yokota M., Young R., Zabaneh D., Zhang F., Zhang R., Zheng W., Zimmet PZ., Altshuler D., Bowden DW., Cho YS., Cox NJ., Cruz M., Hanis CL., Kooner J., Lee J-Y., Seielstad M., Teo YY., Boehnke M., Parra EJ., Chambers JC., Tai ES., McCarthy MI., Morris AP.
To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.