Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Abstract

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Figure 1. Genome-wide association analyses for WHR in discovery studies

A. Manhattan plot shows results of the WHR association meta-analysis in discovery studies (P on the y-axis and SNP genomic position on the x-axis). Colored genomic loci indicate significant association (P < 5 × 10⁻⁸) detected previously (blue), in our GWA stage (red), and after the meta-analysis combining GWA and follow-up studies (orange). Two loci tested in the follow-up stage did not achieve genome-wide significance (green). B. Quantile-quantile (QQ) plot of SNPs for the discovery meta-analysis of WHR (black) and after removing SNPs within 1 Mb of either the recently reported LYPLAL1 signal (blue) or the 14 significant associations (green). The grey area represents the 95% confidence interval around the test statistic under the null distribution.

Figure 2. Regional plots of 14 loci with genome-wide significant association

SNP association with WHR in meta-analysis of discovery studies for 14 loci (−log₁₀ P on the y-axis and SNP genomic position on the x-axis). In each panel, an index SNP is denoted with a purple diamond and plotted using the P attained across discovery and follow-up data (Table 1). Estimated recombination rates are plotted in blue. SNPs are colored to reflect LD with the index SNP (pair-wise r² values from HapMap CEU). Gene and microRNA annotations are from the UCSC genome browser.

Figure 3. Association of the 14 WHR loci with waist and hip circumference

Beta-coefficients for waist circumference (WC, x-axis) and hip circumference (HIP, y-axis) in women and men derived from the joint discovery and follow-up analysis. P for WC and HIP are represented by color. In men, grey gene labels refer to those SNPs that were not significant in the male-specific WHR analysis. More details can be found in Supplementary Table 3.

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