New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Dupuis J., Langenberg C., Prokopenko I., Saxena R., Soranzo N., Jackson AU., Wheeler E., Glazer NL., Bouatia-Naji N., Gloyn AL., Lindgren CM., Mägi R., Morris AP., Randall J., Johnson T., Elliott P., Rybin D., Thorleifsson G., Steinthorsdottir V., Henneman P., Grallert H., Dehghan A., Hottenga JJ., Franklin CS., Navarro P., Song K., Goel A., Perry JRB., Egan JM., Lajunen T., Grarup N., Sparsø T., Doney A., Voight BF., Stringham HM., Li M., Kanoni S., Shrader P., Cavalcanti-Proença C., Kumari M., Qi L., Timpson NJ., Gieger C., Zabena C., Rocheleau G., Ingelsson E., An P., O'Connell J., Luan J., Elliott A., McCarroll SA., Payne F., Roccasecca RM., Pattou F., Sethupathy P., Ardlie K., Ariyurek Y., Balkau B., Barter P., Beilby JP., Ben-Shlomo Y., Benediktsson R., Bennett AJ., Bergmann S., Bochud M., Boerwinkle E., Bonnefond A., Bonnycastle LL., Borch-Johnsen K., Böttcher Y., Brunner E., Bumpstead SJ., Charpentier G., Chen Y-DI., Chines P., Clarke R., Coin LJM., Cooper MN., Cornelis M., Crawford G., Crisponi L., Day INM., de Geus EJC., Delplanque J., Dina C., Erdos MR., Fedson AC., Fischer-Rosinsky A., Forouhi NG., Fox CS., Frants R., Franzosi MG., Galan P., Goodarzi MO., Graessler J., Groves CJ., Grundy S., Gwilliam R., Gyllensten U., Hadjadj S., Hallmans G., Hammond N., Han X., Hartikainen A-L., Hassanali N., Hayward C., Heath SC., Hercberg S., Herder C., Hicks AA., Hillman DR., Hingorani AD., Hofman A., Hui J., Hung J., Isomaa B., Johnson PRV., Jørgensen T., Jula A., Kaakinen M., Kaprio J., Kesaniemi YA., Kivimaki M., Knight B., Koskinen S., Kovacs P., Kyvik KO., Lathrop GM., Lawlor DA., Le Bacquer O., Lecoeur C., Li Y., Lyssenko V., Mahley R., Mangino M., Manning AK., Martínez-Larrad MT., McAteer JB., McCulloch LJ., McPherson R., Meisinger C., Melzer D., Meyre D., Mitchell BD., Morken MA., Mukherjee S., Naitza S., Narisu N., Neville MJ., Oostra BA., Orrù M., Pakyz R., Palmer CNA., Paolisso G., Pattaro C., Pearson D., Peden JF., Pedersen NL., Perola M., Pfeiffer AFH., Pichler I., Polasek O., Posthuma D., Potter SC., Pouta A., Province MA., Psaty BM., Rathmann W., Rayner NW., Rice K., Ripatti S., Rivadeneira F., Roden M., Rolandsson O., Sandbaek A., Sandhu M., Sanna S., Sayer AA., Scheet P., Scott LJ., Seedorf U., Sharp SJ., Shields B., Sigurethsson G., Sijbrands EJG., Silveira A., Simpson L., Singleton A., Smith NL., Sovio U., Swift A., Syddall H., Syvänen A-C., Tanaka T., Thorand B., Tichet J., Tönjes A., Tuomi T., Uitterlinden AG., van Dijk KW., van Hoek M., Varma D., Visvikis-Siest S., Vitart V., Vogelzangs N., Waeber G., Wagner PJ., Walley A., Walters GB., Ward KL., Watkins H., Weedon MN., Wild SH., Willemsen G., Witteman JCM., Yarnell JWG., Zeggini E., Zelenika D., Zethelius B., Zhai G., Zhao JH., Zillikens MC., DIAGRAM Consortium None., GIANT Consortium None., Global BPgen Consortium None., Borecki IB., Loos RJF., Meneton P., Magnusson PKE., Nathan DM., Williams GH., Hattersley AT., Silander K., Salomaa V., Smith GD., Bornstein SR., Schwarz P., Spranger J., Karpe F., Shuldiner AR., Cooper C., Dedoussis GV., Serrano-Ríos M., Morris AD., Lind L., Palmer LJ., Hu FB., Franks PW., Ebrahim S., Marmot M., Kao WHL., Pankow JS., Sampson MJ., Kuusisto J., Laakso M., Hansen T., Pedersen O., Pramstaller PP., Wichmann HE., Illig T., Rudan I., Wright AF., Stumvoll M., Campbell H., Wilson JF., Anders Hamsten on behalf of Procardis Consortium None., MAGIC investigators None., Bergman RN., Buchanan TA., Collins FS., Mohlke KL., Tuomilehto J., Valle TT., Altshuler D., Rotter JI., Siscovick DS., Penninx BWJH., Boomsma DI., Deloukas P., Spector TD., Frayling TM., Ferrucci L., Kong A., Thorsteinsdottir U., Stefansson K., van Duijn CM., Aulchenko YS., Cao A., Scuteri A., Schlessinger D., Uda M., Ruokonen A., Jarvelin M-R., Waterworth DM., Vollenweider P., Peltonen L., Mooser V., Abecasis GR., Wareham NJ., Sladek R., Froguel P., Watanabe RM., Meigs JB., Groop L., Boehnke M., McCarthy MI., Florez JC., Barroso I.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.