Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.
Scott RA., Lagou V., Welch RP., Wheeler E., Montasser ME., Luan J., Mägi R., Strawbridge RJ., Rehnberg E., Gustafsson S., Kanoni S., Rasmussen-Torvik LJ., Yengo L., Lecoeur C., Shungin D., Sanna S., Sidore C., Johnson PCD., Jukema JW., Johnson T., Mahajan A., Verweij N., Thorleifsson G., Hottenga J-J., Shah S., Smith AV., Sennblad B., Gieger C., Salo P., Perola M., Timpson NJ., Evans DM., Pourcain BS., Wu Y., Andrews JS., Hui J., Bielak LF., Zhao W., Horikoshi M., Navarro P., Isaacs A., O'Connell JR., Stirrups K., Vitart V., Hayward C., Esko T., Mihailov E., Fraser RM., Fall T., Voight BF., Raychaudhuri S., Chen H., Lindgren CM., Morris AP., Rayner NW., Robertson N., Rybin D., Liu C-T., Beckmann JS., Willems SM., Chines PS., Jackson AU., Kang HM., Stringham HM., Song K., Tanaka T., Peden JF., Goel A., Hicks AA., An P., Müller-Nurasyid M., Franco-Cereceda A., Folkersen L., Marullo L., Jansen H., Oldehinkel AJ., Bruinenberg M., Pankow JS., North KE., Forouhi NG., Loos RJF., Edkins S., Varga TV., Hallmans G., Oksa H., Antonella M., Nagaraja R., Trompet S., Ford I., Bakker SJL., Kong A., Kumari M., Gigante B., Herder C., Munroe PB., Caulfield M., Antti J., Mangino M., Small K., Miljkovic I., Liu Y., Atalay M., Kiess W., James AL., Rivadeneira F., Uitterlinden AG., Palmer CNA., Doney ASF., Willemsen G., Smit JH., Campbell S., Polasek O., Bonnycastle LL., Hercberg S., Dimitriou M., Bolton JL., Fowkes GR., Kovacs P., Lindström J., Zemunik T., Bandinelli S., Wild SH., Basart HV., Rathmann W., Grallert H., DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium None., Maerz W., Kleber ME., Boehm BO., Peters A., Pramstaller PP., Province MA., Borecki IB., Hastie ND., Rudan I., Campbell H., Watkins H., Farrall M., Stumvoll M., Ferrucci L., Waterworth DM., Bergman RN., Collins FS., Tuomilehto J., Watanabe RM., de Geus EJC., Penninx BW., Hofman A., Oostra BA., Psaty BM., Vollenweider P., Wilson JF., Wright AF., Hovingh GK., Metspalu A., Uusitupa M., Magnusson PKE., Kyvik KO., Kaprio J., Price JF., Dedoussis GV., Deloukas P., Meneton P., Lind L., Boehnke M., Shuldiner AR., van Duijn CM., Morris AD., Toenjes A., Peyser PA., Beilby JP., Körner A., Kuusisto J., Laakso M., Bornstein SR., Schwarz PEH., Lakka TA., Rauramaa R., Adair LS., Smith GD., Spector TD., Illig T., de Faire U., Hamsten A., Gudnason V., Kivimaki M., Hingorani A., Keinanen-Kiukaanniemi SM., Saaristo TE., Boomsma DI., Stefansson K., van der Harst P., Dupuis J., Pedersen NL., Sattar N., Harris TB., Cucca F., Ripatti S., Salomaa V., Mohlke KL., Balkau B., Froguel P., Pouta A., Jarvelin M-R., Wareham NJ., Bouatia-Naji N., McCarthy MI., Franks PW., Meigs JB., Teslovich TM., Florez JC., Langenberg C., Ingelsson E., Prokopenko I., Barroso I.
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.