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Sex differences in the genetic regulation of the human plasma proteome

Author

Listed:
  • Mine Koprulu

    (Precision Healthcare University Research Institute, Queen Mary University of London
    University of Cambridge School of Clinical Medicine, Institute of Metabolic Science)

  • 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
    Health Data Research UK
    British Heart Foundation Data Science Centre
    National Institute of Health Research University College London Hospitals Biomedical Research Centre)

  • Julia Carrasco-Zanini

    (Precision Healthcare University Research Institute, Queen Mary University of London
    University of Cambridge School of Clinical Medicine, Institute of Metabolic Science)

  • Chloe M. Orkin

    (Queen Mary University of London
    Barts Health NHS Trust)

  • Harry Hemingway

    (University College London
    Health Data Research UK
    National Institute of Health Research University College London Hospitals Biomedical Research Centre)

  • 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
    University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
    Berlin Institute of Health at Charité-Universitätsmedizin Berlin)

  • Claudia Langenberg

    (Precision Healthcare University Research Institute, Queen Mary University of London
    University of Cambridge School of Clinical Medicine, Institute of Metabolic Science
    Berlin Institute of Health at Charité-Universitätsmedizin Berlin)

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.

Suggested Citation

  • Mine Koprulu & Eleanor Wheeler & Nicola D. Kerrison & Spiros Denaxas & Julia Carrasco-Zanini & Chloe M. Orkin & Harry Hemingway & Nicholas J. Wareham & Maik Pietzner & Claudia Langenberg, 2025. "Sex differences in the genetic regulation of the human plasma proteome," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59034-4
    DOI: 10.1038/s41467-025-59034-4
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