Summary: An international analysis of roughly 6,000 blood proteins measured in 56,000 people finds widespread differences in protein levels between males and females, but shows that these differences are rarely driven by sex-specific genetics. Only about 100 proteins exhibited sex-specific genetic regulation, indicating that non-genetic influences — including hormones, environment, and social and lifestyle factors — play a large role in shaping sex-based health differences.
The results challenge the assumption that genetic variation alone explains health disparities between males and females and underline the importance of integrating social, environmental and biological factors into precision medicine.
Key facts
- Widespread protein differences: Approximately two-thirds of the proteins examined show statistically significant level differences between sexes.
- Limited sex-specific genetics: Only about 100 proteins out of ~6,000 had sex-differential genetic regulation.
- Role of non-genetic factors: Environmental exposure, hormones, occupation, socioeconomic status and lifestyle are likely major contributors to sex differences in health and should be considered in research and care.
Source: Queen Mary University of London
Study overview
Led by researchers at Queen Mary University of London’s Precision Healthcare University Research Institute (PHURI) in collaboration with the Berlin Institute of Health at Charité and the MRC Epidemiology Unit at the University of Cambridge, this large-scale investigation used protein and genetic data from UK Biobank and the Fenland Study. The team examined links between genetic variation and plasma levels of nearly 6,000 proteins across 56,365 participants (around 30,307 females and 26,058 males).
While plasma concentrations of about two-thirds of the measured protein targets differed by sex, genetic influences on those protein levels were remarkably similar for males and females. Only 103 protein quantitative trait loci (pQTLs) showed sex-differential effects, representing a small fraction of the protein targets tested. A minority of those loci demonstrated sexual discordance — either effects present in just one sex or effects in opposite directions for males and females.
Phenome-wide analyses covering 365 clinical outcomes in UK Biobank found little evidence that these sex-differential pQTLs explain observed sex differences in disease risk. Taken together, the findings suggest that sex-based disparities in protein expression arise mainly from non-genetic factors and that sex-specific genetic regulation is relatively rare.
Implications for research and medicine
These results have practical implications for drug discovery, biomarker development and precision medicine. Many drug-development programs use genetic evidence about protein targets to prioritize and validate candidates. The study shows that, with few exceptions, genetic variants that influence protein levels behave similarly across sexes. This supports the idea that genetically informed target selection can often be applied to both males and females, but it also highlights scenarios where sex-specific biology or non-genetic factors may require tailored approaches.
The authors stress that hormones, social determinants of health, occupational and environmental exposures, education, income and lifestyle choices — factors that differ between individuals and between sexes — deserve greater attention when interpreting sex differences in health and when designing equitable interventions.
Comments from the team
Mine Koprulu, lead author and postdoctoral researcher at PHURI, said this is the largest study to date to evaluate how genetic regulation of blood protein levels differs between sexes. She emphasized the need to study both genetic and non-genetic contributors to health differences to improve personalized and equitable healthcare.
Professor Claudia Langenberg, Director of PHURI and Professor of Computational Medicine at the Berlin Institute of Health at Charité, noted that understanding how protein regulation varies across populations is essential for precision medicine. The study’s overall finding — that most protein-regulating genetic variants act similarly in both sexes — supports the generalizability of many genetic insights, while also calling attention to the few exceptions where sex-specific effects occur.
For the purposes of the genetic and proteomic analyses, participants were categorized as male or female based on chromosomal information (XX or XY). The authors acknowledge that chromosomal sex does not always match individual gender identity; however, consistent, reliable gender identity data were not available across all datasets for this analysis.
Funding and acknowledgements
The Fenland Study is supported by the Medical Research Council. Additional funding and support were provided by various MRC grants, Gates Cambridge Trust (supporting Mine Koprulu), Health Data Research UK and NIHR University College London Hospitals Biomedical Research Centre (supporting Harry Hemingway), and multiple supporting consortia and awards for other investigators. Julia Carrasco-Zanini received support from a Wellcome Trust PhD Studentship and the Cambridge Trust. The authors thank all participants in the Fenland Study and UK Biobank whose contributions made the work possible.
About this genetics research news
Author: Honey Lucas
Source: Queen Mary University London
Contact: Honey Lucas – Queen Mary University London
Image: Image credited to Neuroscience News
Original research (open access):
“Sex differences in the genetic regulation of the human plasma proteome” by Mine Koprulu et al., published in Nature Communications. DOI: 10.1038/s41467-025-59034-4
Abstract
Sex differences in the genetic regulation of the human plasma proteome
Mechanisms underlying sex differences in the development and prognosis of many diseases remain largely elusive. This study systematically investigated sex differences in the genetic regulation of the plasma proteome (more than 5,800 protein targets) across two cohorts totaling 30,307 females and 26,058 males. Plasma levels for about two-thirds of protein targets differed significantly by sex, yet genetic effects were largely similar across sexes. Only 103 sex-differential protein quantitative trait loci (sd-pQTLs) were identified, representing 2.9% and 0.3% of proteins on antibody- and aptamer-based platforms, respectively. A subset of these showed sexual discordance, with effects seen only in one sex or with opposite directions between sexes. Phenome-wide analyses across 365 outcomes did not suggest that the identified sd-pQTLs explain sex-differential disease risk. The results demonstrate broad similarities in genetic regulation of protein levels by sex and carry important implications for genetically guided drug target discovery and validation.