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Genome-wide association study of the modified Stumvoll Insulin Sensitivity Index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci.

Diabetes 65, 3200-3211 (2016)
Publishers Version Postprint DOI PMC
Open Access Green
as soon as is submitted to ZB.
Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-related traits Consortium. Discovery was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, body mass index (BMI) and in a model ("Model 3") analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI. In Model 3, three variants reached genome-wide significance: rs13422522 (NYAP2, P=8.87 ×10(-11)), rs12454712 (BCL2, P=2.7×10(-8)) and rs10506418 (FAM19A2, P=1.9×10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardio-metabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Glucose-tolerance Test; Euglycemic Clamp; Glycemic Traits; Metaanalysis; Gene; Pathophysiology; Heritability; Resistance; Release; Snp
Reviewing status