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.
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A full list of Acknowledgments appears in the Supplementary Note.
J.B.M. currently has research grants from GlaxoSmithKline and Sanofi-Aventis, and serves on consultancy boards for Eli Lilly and Interleukin Genetics. J.C.F. has received consulting honoraria from Merck, Pfizer, bioStrategies, XOMA and Publicis Healthcare Communications Group, a global advertising agency engaged by Amylin Pharmaceuticals. deCODE authors are employees at deCODE genetics and own stock or stock options in the company. P.W.F. has received consulting honoraria from Unilever. P.V. and G.W. received financial support from GlaxoSmithKline to build the CoLaus study. V.M., K.S. and D.M.W. are all full-time employees at GlaxoSmithKline. I.B. and spouse own stock in GlaxoSmithKline and Incyte.
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Dupuis, J., Langenberg, C., Prokopenko, I. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42, 105–116 (2010). https://doi.org/10.1038/ng.520
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