Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
Gaulton KJ., Ferreira T., Lee Y., Raimondo A., Mägi R., Reschen ME., Mahajan A., Locke A., Rayner NW., Robertson N., Scott RA., Prokopenko I., Scott LJ., Green T., Sparso T., Thuillier D., Yengo L., Grallert H., Wahl S., Frånberg M., Strawbridge RJ., Kestler H., Chheda H., Eisele L., Gustafsson S., Steinthorsdottir V., Thorleifsson G., Qi L., Karssen LC., van Leeuwen EM., Willems SM., Li M., Chen H., Fuchsberger C., Kwan P., Ma C., Linderman M., Lu Y., Thomsen SK., Rundle JK., Beer NL., van de Bunt M., Chalisey A., Kang HM., Voight BF., Abecasis GR., Almgren P., Baldassarre D., Balkau B., Benediktsson R., Blüher M., Boeing H., Bonnycastle LL., Bottinger EP., Burtt NP., Carey J., Charpentier G., Chines PS., Cornelis MC., Couper DJ., Crenshaw AT., van Dam RM., Doney ASF., Dorkhan M., Edkins S., Eriksson JG., Esko T., Eury E., Fadista J., Flannick J., Fontanillas P., Fox C., Franks PW., Gertow K., Gieger C., Gigante B., Gottesman O., Grant GB., Grarup N., Groves CJ., Hassinen M., Have CT., Herder C., Holmen OL., Hreidarsson AB., Humphries SE., Hunter DJ., Jackson AU., Jonsson A., Jørgensen ME., Jørgensen T., Kao W-HL., Kerrison ND., Kinnunen L., Klopp N., Kong A., Kovacs P., Kraft P., Kravic J., Langford C., Leander K., Liang L., Lichtner P., Lindgren CM., Lindholm E., Linneberg A., Liu C-T., Lobbens S., Luan J., Lyssenko V., Männistö S., McLeod O., Meyer J., Mihailov E., Mirza G., Mühleisen TW., Müller-Nurasyid M., Navarro C., Nöthen MM., Oskolkov NN., Owen KR., Palli D., Pechlivanis S., Peltonen L., Perry JRB., Platou CGP., Roden M., Ruderfer D., Rybin D., van der Schouw YT., Sennblad B., Sigurðsson G., Stančáková A., Steinbach G., Storm P., Strauch K., Stringham HM., Sun Q., Thorand B., Tikkanen E., Tonjes A., Trakalo J., Tremoli E., Tuomi T., Wennauer R., Wiltshire S., Wood AR., Zeggini E., Dunham I., Birney E., Pasquali L., Ferrer J., Loos RJF., Dupuis J., Florez JC., Boerwinkle E., Pankow JS., van Duijn C., Sijbrands E., Meigs JB., Hu FB., Thorsteinsdottir U., Stefansson K., Lakka TA., Rauramaa R., Stumvoll M., Pedersen NL., Lind L., Keinanen-Kiukaanniemi SM., Korpi-Hyövälti E., Saaristo TE., Saltevo J., Kuusisto J., Laakso M., Metspalu A., Erbel R., Jöcke K-H., Moebus S., Ripatti S., Salomaa V., Ingelsson E., Boehm BO., Bergman RN., Collins FS., Mohlke KL., Koistinen H., Tuomilehto J., Hveem K., Njølstad I., Deloukas P., Donnelly PJ., Frayling TM., Hattersley AT., de Faire U., Hamsten A., Illig T., Peters A., Cauchi S., Sladek R., Froguel P., Hansen T., Pedersen O., Morris AD., Palmer CNA., Kathiresan S., Melander O., Nilsson PM., Groop LC., Barroso I., Langenberg C., Wareham NJ., O'Callaghan CA., Gloyn AL., Altshuler D., Boehnke M., Teslovich TM., McCarthy MI., Morris AP., DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium None.
We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.