Sex-related signatures in the plasma proteome not attributable to XX and XY chromosomes and their impact on health and disease
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Sex differences in human health are typically modeled as binary comparisons between males (XY) and females (XX). However, sex-linked molecular traits vary continuously and are shaped by environmental factors. Here, we introduce the Proteomic Sex Index (PSI), a continuous, plasma proteomics–based measure that quantifies the degree to which an individual’s proteome aligns with their chromosomal sex, with higher PSI values indicating profiles less typical for their sex. Leveraging data from 51,310 individuals from six demographically heterogeneous cohorts, we show that PSI captures broad, biologically meaningful variation in sex-enriched traits and diseases. Individuals with proteomic profiles shifted away from their chromosomal sex exhibited trait values less characteristic of that sex. For example, males with higher PSI were shorter, had lower grip strength, and showed reduced severity of COVID-19 (OR=0.59, p =3.0×10 −7 ). Analyses of individuals undergoing gender-affirming hormone therapy showed that, although PSI correlated with circulating sex hormones, it also captured additional variation independent of hormone levels. PSI is partially heritable and genetically influenced. Individuals with Klinefelter syndrome (XXY) had markedly elevated PSI (OR=13.7, p =1.1×10 −13 ), and genome-wide association studies of PSI identified sex-biased cis-pQTLs with evidence of causal links to sex-specific disease risk. PSI provides a nuanced, individualized measure of sex-related biology that enables the study of within-sex molecular variation and its links to health and disease.
Source: medRxiv
Authors: Essi Viippola, Tuomo Hartonen, Meihui Zhu, Zhijian Yang, Ryuya Edahiro, Tomoko Nakanishi, Ao Lan, Masahiro Kanai, Nhi N. L. Nguyen, Tatiana Cajuso, Daniela Fusco, Chiara Caime, Kristina Zguro, Sebastian May-Wilson, M. Austin Argentieri, Gabin Drouard, Lisa Eick, Matteo Ferro, Aoxing Liu, Rodosthenis Rodosthenous, FinnGen, Biobank Japan, Japan COVID-19 Task Force, Jarno Honkanen, Jukka Partanen, Miina Ollikainen, Jaakko Kaprio, Ho Namkoong, Koichi Fukunaga, Koichi Matsuda, Jerome I. Rotter, Stephen S. Rich, Kent D. Taylor, Robert E. Gerszten, Clary Clish, Peter Y. Liu, Alexis C. Wood, Craig Johnson, Ada S. Cheung, Tamar Sofer, Mark Daly, Taru Tukiainen, Boris Novakovic, Yukinori Okada, Xia Shen, Andrea Ganna
Institutions: Broad Institute, University of Helsinki, Massachusetts General Hospital, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, RIKEN Center for Integrative Medical Sciences, The University of Osaka, Queen Mary University of London, The University of Tokyo, Fudan University, State Key Laboratory of Genetic Engineering, Greater Bay Area Institute of Precision Medicine, Stanley Center for Psychiatric Research, Royal Children's Hospital, Murdoch Children's Research Institute, University of Turin, University of Milano-Bicocca, Baylor College of Medicine, Children's Nutrition Research Center at Baylor College of Medicine, Finnish Red Cross, Minerva Foundation, Keio University, Keio University Hospital, Institute of Medical Science, The University of Tokyo, The Lundquist Institute, Harbor–UCLA Medical Center, University of Virginia, Beth Israel Deaconess Medical Center, Agricultural Research Service, University of Washington, The University of Melbourne, Austin Hospital, Austin Health, Harvard University, University of Eastern Finland, Karolinska Institutet
Language: English
Topic: Sex and Gender in Healthcare
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7223144538