Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
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A full list of acknowledgments is provided in the Supplementary Note.
J.C.F. has received consulting fees from Novartis, Eli Lilly and Pfizer. I.B. and spouse own stock in GlaxoSmithKline and Incyte Ltd. A.R.S. is a consultant for Merck.
Supplementary Note and Supplementary Figures 1–3 (PDF 1606 kb)
Study descriptives of samples included in meta-analysis (XLS 106 kb)
Meta-analysis results of loci with known associations with glycemic traits (XLS 71 kb)
Meta-analysis results of fasting insulin and fasting glucose loci taken to the follow-up stage of analysis (XLS 225 kb)
Association results of index SNPs with other traits (HOMA-IR, HOMA-B, 2hr glucose, and HbA1c) in MAGIC (XLS 33 kb)
eQTL SNPs in linkage disequilibrium with fasting insulin index SNPs in gene expression database from liver tissue (XLS 41 kb)
Fasting insulin index SNPs in gene expression eQTL database from subcutaneous adipose tissue (MuTHER). (XLS 46 kb)
Details of coding SNPs (cSNPs) near index SNPs. (XLS 56 kb)
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Manning, A., Hivert, MF., Scott, R. et al. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet 44, 659–669 (2012). https://doi.org/10.1038/ng.2274
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