Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution

Abstract

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

Figure 1. Project outline.

We started out with a meta-analysis of GWAS data from 16 cohorts comprising 38,580 individuals informative for WC and 37,670 for WHR. We selected 23 SNPs of our top signals based on the following criteria (Table S2): preliminary stage 1 meta-analysis P-value≤10⁻⁵, BMI P-value>0.01 and height P-value>5×10⁻³. We supplemented these 23 independent loci (r²<0.2) SNPs with three additional candidate signals. Further, we excluded recently reported BMI loci (Table S10) , , –. These 26 SNPs were followed up in our stage 2 samples (N = maximum of 70,689 individuals). Further, we sought to confirm WC signals reaching genome wide significance in the combined analysis of stage 1 and 2 data in GWA data from the CHARGE consortium (for which WHR was not available). The data from the Rotterdam and ERF cohorts (up to 6,702 individuals) which were included in both CHARGE and stage 2 data, were counted only once in the overall analysis.

Figure 2. Genome-wide association results for GIANT (Stage 1).

A. Manhattan plots showing significance of association of all SNPs in the Stage 1 GIANT meta-analysis with central obesity phenotypes. SNPs are plotted on the x-axis according to their position on each chromosome against association with central obesity measure (WC or WHR) on the y-axis (shown as −log10 P-value). SNPs that have been previously reported to show association with BMI is shown in blue ,, and the two regions showing strong associations in the overall, non-gender-stratified analyses are shown in green. Other SNPs taken forward into stage 2 follow-up are indicated in red. B. Quantile-quantile (QQ) plots of SNPs; after Stage 1 GIANT meta-analysis (black) and after removing any SNPs surrounding the recently reported BMI loci , , – (blue). The grey areas in the QQ plots represent the 95% confidence intervals around the test statistics and after excluding the recently reported BMI loci , , –, there is no indication of excess of signal.

Figure 3. Regional plots of loci highlighted in this study.

SNPs are plotted by position on chromosome against association (−log10 p-value) with central obesity phenotype (WC or WHR) using stage 1 (GWAS meta-analysis) data. In the case of panel (b), analyses are restricted to women only. In each panel, the SNP with the strongest association based on stage 1 data is denoted with a purple diamond: the P-value attached represents the final P-value attained across all available data (Table 1). Estimated recombination rates (from HapMap-CEU) are plotted in purple to reflect the local LD structure on a secondary Y-axis. The SNPs surrounding the most significant SNP (purple diamond) are color-coded (see inset) to reflect their LD with this SNP (using pair-wise r² values from HapMap CEU). Genes and the position of exons, as well as the direction of transcription, are shown below the plots (using data from the UCSC genome browser, genome.ucsc.edu). The grey area marks the extent of the region that includes any SNP with r²≥0.3 relative to the SNP with the strongest stage 1 association signal. Hash marks represent SNP positions on each genotyping array used by any individual study and also show SNP positions after imputation.