Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Morris AP., Voight BF., Teslovich TM., Ferreira T., Segrè AV., Steinthorsdottir V., Strawbridge RJ., Khan H., Grallert H., Mahajan A., Prokopenko I., Kang HM., Dina C., Esko T., Fraser RM., Kanoni S., Kumar A., Lagou V., Langenberg C., Luan J., Lindgren CM., Müller-Nurasyid M., Pechlivanis S., Rayner NW., Scott LJ., Wiltshire S., Yengo L., Kinnunen L., Rossin EJ., Raychaudhuri S., Johnson AD., Dimas AS., Loos RJF., Vedantam S., Chen H., Florez JC., Fox C., Liu C-T., Rybin D., Couper DJ., Kao WHL., Li M., Cornelis MC., Kraft P., Sun Q., van Dam RM., Stringham HM., Chines PS., Fischer K., Fontanillas P., Holmen OL., Hunt SE., Jackson AU., Kong A., Lawrence R., Meyer J., Perry JRB., Platou CGP., Potter S., Rehnberg E., Robertson N., Sivapalaratnam S., Stančáková A., Stirrups K., Thorleifsson G., Tikkanen E., Wood AR., Almgren P., Atalay M., Benediktsson R., Bonnycastle LL., Burtt N., Carey J., Charpentier G., Crenshaw AT., Doney ASF., Dorkhan M., Edkins S., Emilsson V., Eury E., Forsen T., Gertow K., Gigante B., Grant GB., Groves CJ., Guiducci C., Herder C., Hreidarsson AB., Hui J., James A., Jonsson A., Rathmann W., Klopp N., Kravic J., Krjutškov K., Langford C., Leander K., Lindholm E., Lobbens S., Männistö S., Mirza G., Mühleisen TW., Musk B., Parkin M., Rallidis L., Saramies J., Sennblad B., Shah S., Sigurðsson G., Silveira A., Steinbach G., Thorand B., Trakalo J., Veglia F., Wennauer R., Winckler W., Zabaneh D., Campbell H., van Duijn C., Uitterlinden AG., Hofman A., Sijbrands E., Abecasis GR., Owen KR., Zeggini E., Trip MD., Forouhi NG., Syvänen A-C., Eriksson JG., Peltonen L., Nöthen MM., Balkau B., Palmer CNA., Lyssenko V., Tuomi T., Isomaa B., Hunter DJ., Qi L., Wellcome Trust Case Control Consortium None., Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Investigators None., Genetic Investigation of ANthropometric Traits (GIANT) Consortium None., Asian Genetic Epidemiology Network–Type 2 Diabetes (AGEN-T2D) Consortium None., South Asian Type 2 Diabetes (SAT2D) Consortium None., Shuldiner AR., Roden M., Barroso I., Wilsgaard T., Beilby J., Hovingh K., Price JF., Wilson JF., Rauramaa R., Lakka TA., Lind L., Dedoussis G., Njølstad I., Pedersen NL., Khaw K-T., Wareham NJ., Keinanen-Kiukaanniemi SM., Saaristo TE., Korpi-Hyövälti E., Saltevo J., Laakso M., Kuusisto J., Metspalu A., Collins FS., Mohlke KL., Bergman RN., Tuomilehto J., Boehm BO., Gieger C., Hveem K., Cauchi S., Froguel P., Baldassarre D., Tremoli E., Humphries SE., Saleheen D., Danesh J., Ingelsson E., Ripatti S., Salomaa V., Erbel R., Jöckel K-H., Moebus S., Peters A., Illig T., de Faire U., Hamsten A., Morris AD., Donnelly PJ., Frayling TM., Hattersley AT., Boerwinkle E., Melander O., Kathiresan S., Nilsson PM., Deloukas P., Thorsteinsdottir U., Groop LC., Stefansson K., Hu F., Pankow JS., Dupuis J., Meigs JB., Altshuler D., Boehnke M., McCarthy MI., DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium None.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.