Sex differences in the genetic regulation of the human plasma proteome

Mine Koprulu, Eleanor Wheeler, Nicola D. Kerrison, Spiros Denaxas, Julia Carrasco-Zanini, Chloe M. Orkin, Harry Hemingway, Nicholas J. Wareham, Maik Pietzner and Claudia Langenberg ()
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Mine Koprulu: Precision Healthcare University Research Institute, Queen Mary University of London
Eleanor Wheeler: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
Nicola D. Kerrison: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
Spiros Denaxas: University College London
Julia Carrasco-Zanini: Precision Healthcare University Research Institute, Queen Mary University of London
Chloe M. Orkin: Queen Mary University of London
Harry Hemingway: University College London
Nicholas J. Wareham: University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
Maik Pietzner: Precision Healthcare University Research Institute, Queen Mary University of London
Claudia Langenberg: Precision Healthcare University Research Institute, Queen Mary University of London

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59034-4

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