Sex-related signatures in the plasma proteome not attributable to XX and XY chromosomes and their impact on health and disease
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 individuals 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=3.0x10-7). 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=1.1x10-13), 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.
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BibTeX
@misc{viippola2026sexrelated,
title = {{Sex-related signatures in the plasma proteome not attributable to XX and XY chromosomes and their impact on health and disease}},
author = {E. Viippola and T. Hartonen and M. Zhu and Z. Yang and R. Edahiro and T. Nakanishi and A. Lan and M. Kanai and N. N. L. Nguyen and T. Cajuso and D. Fusco and C. Caime and K. Zguro and S. May-Wilson and M. A. Argentieri and G. Drouard and L. Eick and M. Ferro and A. Liu and R. Rodosthenous and FinnGen and Biobank Japan and Japan COVID-19 Task Force and J. Honkanen and J. Partanen and M. Ollikainen and J. Kaprio and H. Namkoong and K. Fukunaga and K. Matsuda and J. Rotter and S. S. Rich and K. D. Taylor and R. E. Gerszten and C. B. Clish and P. Y. Liu and A. C. Wood and C. Johnson and A. S. Cheung and T. Sofer and M. J. Daly and T. Tukiainen and B. Novakovic and Y. Okada},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.26365875},
url = {https://www.medrxiv.org/content/10.64898/2026.10.19.26365875v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Sex-related signatures in the plasma proteome not attributable to XX and XY chromosomes and their impact on health and disease
AU - E. Viippola
AU - T. Hartonen
AU - M. Zhu
AU - Z. Yang
AU - R. Edahiro
AU - T. Nakanishi
AU - A. Lan
AU - M. Kanai
AU - N. N. L. Nguyen
AU - T. Cajuso
AU - D. Fusco
AU - C. Caime
AU - K. Zguro
AU - S. May-Wilson
AU - M. A. Argentieri
AU - G. Drouard
AU - L. Eick
AU - M. Ferro
AU - A. Liu
AU - R. Rodosthenous
AU - FinnGen
AU - Biobank Japan
AU - Japan COVID-19 Task Force
AU - J. Honkanen
AU - J. Partanen
AU - M. Ollikainen
AU - J. Kaprio
AU - H. Namkoong
AU - K. Fukunaga
AU - K. Matsuda
AU - J. Rotter
AU - S. S. Rich
AU - K. D. Taylor
AU - R. E. Gerszten
AU - C. B. Clish
AU - P. Y. Liu
AU - A. C. Wood
AU - C. Johnson
AU - A. S. Cheung
AU - T. Sofer
AU - M. J. Daly
AU - T. Tukiainen
AU - B. Novakovic
AU - Y. Okada
PY - 2026
DA - 2026/10/19
PB - medRxiv
DO - 10.64898/2026.10.19.26365875
UR - https://www.medrxiv.org/content/10.64898/2026.10.19.26365875v1
AB - 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 individuals 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=3.0x10-7). 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=1.1x10-13), 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.
ER -