Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

Abstract

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

Figure 1

Manhattan plot showing the significance of association with body fat percentage for all SNPs in the stage 1 meta-analysis of all individuals (n=36,626). SNPs are plotted on the x-axis according to their position on each chromosome against association with body fat percentage on the y-axis (shown as −log₁₀ P-value). The loci highlighted in blue are the 11 loci that reached an association P value < 10⁻⁶ in the stage 1 meta-analysis of all individuals, Europeans, men, or women, and were taken forward for follow-up analyses, but did not achieve genome-wide significance (P < 5 × 10⁻⁸) in the meta-analyses combining GWAS and follow-up data. The three loci coloured in red are those that reached genome-wide significant association (P < 5 × 10⁻⁸) in the meta-analyses combining GWAS and follow-up data.

Figure 2

Regional plot of the loci near IRS1, near SPRY2, and in FTO that reached genome-wide significant evidence for association with body fat percentage. The plotted data for the near-SPRY2 locus are from the meta-analysis of individuals of European descent only, and the data for the near-IRS1 and FTO loci are from the meta-analysis of all individuals. The rs2943650 (near-IRS1), rs534870 (near-SPRY2), and rs8050136 (FTO) SNPs which showed the strongest association with body fat percentage are indicated. For the near-IRS1 locus, the rs2972146, rs2943641, and rs2943634 SNPs, which have been associated with blood levels of HDL cholesterol and triglycerides, risk of type 2 diabetes and risk of coronary artery disease, respectively, in meta-analyses of genome-wide association studies are also indicated. The plot was generated using LocusZoom (see URLs).

Figure 3

Association of the body fat percentage decreasing (T) allele of rs2943650 near IRS1 with blood lipids, insulin sensitivity traits, leptin and adiponectin. The error bars indicate 95% confidence intervals. All traits were inverse normally transformed to approximate normality (mean = 0, sd = 1) in men and women separately. All models were adjusted for age and age squared. The numeric values for the associations are presented in Supplementary Table 6. A significant difference between men and women was found for the levels of HDL cholesterol (P = 0.027), triglycerides (P = 0.025), and adiponectin (P = 0.040). InsAUC / GluAUC, insulin area under the curve (AUC) / glucose AUC ratio.