Sex differences in the genetic regulation of the human plasma proteome

作者：Mine Koprulu, Eleanor Wheeler, Nicola D. Kerrison, Spiros Denaxas, Julia Carrasco-Zanini, Chloe Orkin, Harry Hemingway, Nicholas J. Wareham, Maik Pietzner, Claudia Langenberg · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59034-4 · 被引用次数：18 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Genetic Associations and Epidemiology、Receptor Mechanisms and Signaling

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.