Sex differences in the genetic architecture of clinical quantitative traits in the electronic health record
- 1Icahn School of Medicine at Mount Sinai
Abstract
Sex differences exist in complex diseases, but the genetic architecture of sex differences in quantitative clinical traits is understudied. Here, we performed sex-stratified genome-wide association studies of 508 clinical traits from electronic health records (EHRs) in 64,956 European-ancestry individuals in the Vanderbilt biobank, BioVU, with replication in the UK Biobank and Colorado Center for Personalized Medicine biobank. Most trait distributions differed significantly by sex. We identified a female-specific locus for erythrocyte distribution width at PIEZO1 and sex-differentiated effect magnitudes at APOE (LDL cholesterol) and SLC2AS (uric acid) that replicated across biobanks, varied with age, and partially mediated associations with heart disease and gout. Opposite-direction sex effects were less replicable. Ascertainment bias could be addressed using inverse-probability weighting. Sex-stratified colocalization with eOTLs nominated additional candidate genes. Differential effect magnitude, not opposing effects, predominate in sex- specific genetic architecture, requiring large sample sizes for discovery that can be achieved using EHR data.
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BibTeX
@misc{blostein2026differences,
title = {{Sex differences in the genetic architecture of clinical quantitative traits in the electronic health record}},
author = {F. A. Blostein and B. Bose and A. Hill and K. Actkins and A. M. Lake and N. Freilich and P. Straub and M. Niarchou and B. E. Stranger and L. K. Davis},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.26362069},
url = {https://www.medrxiv.org/content/10.64898/2026.09.02.26362069v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Sex differences in the genetic architecture of clinical quantitative traits in the electronic health record
AU - F. A. Blostein
AU - B. Bose
AU - A. Hill
AU - K. Actkins
AU - A. M. Lake
AU - N. Freilich
AU - P. Straub
AU - M. Niarchou
AU - B. E. Stranger
AU - L. K. Davis
PY - 2026
DA - 2026/09/02
PB - medRxiv
DO - 10.64898/2026.09.02.26362069
UR - https://www.medrxiv.org/content/10.64898/2026.09.02.26362069v1
AB - Sex differences exist in complex diseases, but the genetic architecture of sex differences in quantitative clinical traits is understudied. Here, we performed sex-stratified genome-wide association studies of 508 clinical traits from electronic health records (EHRs) in 64,956 European-ancestry individuals in the Vanderbilt biobank, BioVU, with replication in the UK Biobank and Colorado Center for Personalized Medicine biobank. Most trait distributions differed significantly by sex. We identified a female-specific locus for erythrocyte distribution width at PIEZO1 and sex-differentiated effect magnitudes at APOE (LDL cholesterol) and SLC2AS (uric acid) that replicated across biobanks, varied with age, and partially mediated associations with heart disease and gout. Opposite-direction sex effects were less replicable. Ascertainment bias could be addressed using inverse-probability weighting. Sex-stratified colocalization with eOTLs nominated additional candidate genes. Differential effect magnitude, not opposing effects, predominate in sex- specific genetic architecture, requiring large sample sizes for discovery that can be achieved using EHR data.
ER -