Sex Differences in Health Driven by More Than Genes

The study, carried out in collaboration with the Berlin Institute of Health at Charité (BIH), and the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, was published today in Nature Communications. Using data from UK Biobank and the Fenland study, the team carried an in-depth analysis of the genetic links between ~6,000 proteins and hundreds of diseases in 56,000 males and females.  

The team found that for two-thirds of these proteins, their levels differed between males and females. Further examination revealed that only a very small fraction, around 100 proteins out of the 6,000 studied, had differences in the genetic "switches" that control their levels when compared between males and females.  

These findings, which may have implications for drug development, indicate that while there are differences between the sexes in relation to how much they express certain proteins, what’s causing these differences isn’t solely down to differences in their genetics.  

Instead, the authors highlight the importance of looking beyond genetics – and other medical factors such as hormones – when comparing health risks and outcomes between males and females. Their findings indicate that non-medical factors such as where people work and live, their education, financial situation, access to resources, as well as their lifestyle also contribute to the health differences experiences between the sexes and so should be explored further and considered more when exploring sex differences in health. 

Mine Koprulu, lead author of the study and a postdoctoral researcher at Queen Mary’s PHURI, said: “For the first time in history, we are able to study human biology at this level of detail—across genes, proteins, and more. This is the largest study to date exploring the similarities and differences in how our genetic code regulates blood protein levels between sexes. Our findings highlight the need to better understand the factors that impact health differences — at the genetic level and beyond— to create more tailored and equitable healthcare for everyone.” 

Professor Claudia Langenberg, Director of the PHURI at Queen Mary and Professor of Computational Medicine at the Berlin Institute of Health at Charité, Germany, said:  

“Drug development pipelines increasingly incorporate information on genetic differences in protein levels and function and this has led to large investment in human cohorts, such as UK Biobank. From this perspective, a better understanding of population differences in the regulation of proteins, such as those between males and females, is essential to guide precision medicine approaches and identify where one size may not fit all. Our results clearly show that with very few exceptions, protein-regulating genetic variants identified so far behave in a very similar way in males and females. This provides evidence for an important implicit assumption – that insights arising from studying these variants apply to both sexes.” 

In this study, data was categorized as male or female based on chromosomal information (XX or XY). The authors acknowledge that chromosomal information does not always align with an individual’s gender identity. However, for the purposes of this study (genetic and protein-level scientific analyses), this categorization was necessary, and data on gender identity was not reliably recorded meaning it could not be consistently used across all data. 

Reference: Koprulu M, Wheeler E, Kerrison ND, et al. Sex differences in the genetic regulation of the human plasma proteome. Nat Commun. 2025;16(1):4001. doi: 10.1038/s41467-025-59034-4

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