Abstract
Mechanisms underlying sex differences in the development and prognosis of many diseases remain largely elusive. Here, we systematically investigated sex differences in the genetic regulation of plasma proteome (>5800 protein targets) across two cohorts (30,307 females; 26,058 males). Plasma levels of two-thirds of protein targets differ significantly by sex. In contrast, genetic effects on protein targets are remarkably similar across sexes, with only 103 sex-differential protein quantitative loci (sd-pQTLs; for 2.9% and 0.3% of protein targets from antibody- and aptamer-based platforms, respectively). A third of those show evidence of sexual discordance, i.e., effects observed in one sex only (n = 30) or opposite effect directions (n = 1 for CDH15). Phenome-wide analyses of 365 outcomes in UK Biobank did not provide evidence that the identified sd-pQTLs accounted for sex-differential disease risk. Our results demonstrate similarities in the genetic regulation of protein levels by sex with important implications for genetically-guided drug target discovery and validation.