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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.

Original publication

DOI

10.1038/ng.520

Type

Journal article

Journal

Nature genetics

Publication Date

02/2010

Volume

42

Pages

105 - 116

Addresses

Department of Biostatistics, Boston University School of Public Health, Massachusetts, USA.

Keywords

DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Blood Glucose, Fasting, Reproducibility of Results, Gene Expression Regulation, Homeostasis, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Databases, Genetic, Adolescent, Adult, Child, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, DNA Copy Number Variations