Sex-heterogeneous SNPs disproportionately influence gene expression and health

Author summaryRisk for many diseases and related manifestations differs by sex. Here, we build on prior work to study a large set of anthropometric and biometric traits that could inform health differences by sex. We define a well-powered list of 2,320 sex-het SNPs showing sex-heterogeneity across multiple traits. We find that sex-het SNPs influence a large set of diseases and health-related traits. The sex-het SNPs are in/near genes with roles in skeletal and muscle development and are involved in regulating gene expression and DNA methylation, two important functions of the genome. We conclude that genetic variation with sexually dimorphic effects on biometric traits not only contributes to fundamental embryogenic processes but plays a role in disease risk later in life and is involved in the regulation of gene expression and epigenetic processes. Our results suggest that sex-heterogeneous SNPs link human physiology and pathology. Phenotypic differences across sexes are pervasive, but the genetic architecture of sex differences within and across phenotypes is mostly unknown. In this study, we aimed to improve detection power for sex-differentially contributing SNPs previously demonstrated to be enriched in disease association, and we investigate their functions in health, pathophysiology, and genetic function. We leveraged GIANT and UK Biobank summary statistics and defined a set of 2,320 independent SNPs having sexually dimorphic effects within and across biometric traits (MAF > 0.001, P < 5x10(-8)). Biometric trait sex-heterogeneous SNPs (sex-het SNPs) showed enrichment in association signals for 20 out of 33 diseases/traits at 5% alpha compared to sex-homogeneous matched SNPs (empP < 0.001), and were significantly overrepresented in muscle, skeletal and stem cell development processes, and in calcium channel and microtubule complexes (FDR < 0.05, empP < 0.05). Interestingly, we found that sex-het SNPs significantly map to predicted expression quantitative trait loci (Pr-eQTLs) across brain and other tissues, methylation quantitative trait loci (meQTLs) during development, and transcription start sites, compared to sex-homogeneous SNPs. Finally, we verified that the sex-het disease/trait enrichment was not explained by Pr-eQTL enrichment alone, as sex-het Pr-eQTLs were more enriched than matched sex-homogeneous Pr-eQTLs. We conclude that genetic polymorphisms with sexually dimorphic effects on biometric traits not only contribute to fundamental embryogenic processes, but later in life play an outsized role in disease risk. These sex-het SNPs disproportionately influence gene expression and have a greater influence on disorders of body and brain than other expression-regulatory variation. Together, our data emphasize the genetic underpinnings of sexual dimorphism and its role in human health.