Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits

Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Figure 1. Genome-wide scan for sex-specific genome-wide association highlights numerous loci.

(a) Manhattan plot showing the men-specific (upward, up to 60,586 men) and women-specific (downward, up to 73,137 women) association P-values from the discovery with the 619 selected loci colored by the phenotype for which the locus was selected; (b) QQ-plot showing the sex-specific association P-values as observed against those expected under the null overall phenotypes (black) and for each phenotypes separately (colored).

Figure 2. Genome-wide sex-difference scan fails to pinpoint loci.

(a) Manhattan plot showing sex-difference P-values, (b) QQ plot for sex-difference P-values overall phenotypes (black) and for each phenotype separately (colored).

Figure 3. Overview of design and findings.

Among the 7 identified loci, we defined those close to (<1 cM) published hits , , as near published hits and novel otherwise. Novel loci with sex-combined discovery P-value<5.8×10⁻⁵, which is the P-value cut-off corresponding to 5% FDR, were declared as loci that could have been discovered also with sex-combined analysis, and otherwise that these would have been missed without the sex-stratified analyses. FDR = false discovery rate.

Figure 4. Consistently higher effect sizes for women for all seven loci.

Shown are beta-estimates and 95% confidence intervals for the seven identified SNPs (also stating the phenotype for which the SNP was selected for).