ArticlePLoS genetics2022
Sex-heterogeneous SNPs disproportionately influence gene expression and health.
Article in PLoS genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 17 citations in OpenAlex.
- Transcriptional mechanisms of sex-biased gene expression and their connections to disease-associated variation.Human molecular genetics · 2026Article
- Integrated analysis of GWAS and molQTLs reveals cell-specific genetic variants in the porcine immune system.Communications biology · 2026Article
- Estradiol and dihydrotestosterone exert sex-specific effects on human fibroblast and endothelial proliferation, bioenergetics, and vasculogenesis.Communications biology · 2025Article
- Genetic Architecture of Immune Cell DNA Methylation in the Rhesus Macaque.Molecular ecology · 2025Article
- Article
- Tradeoffs in Modeling Context Dependency in Complex Trait Genetics.bioRxiv : the preprint server for biology · 2025Article
- Long-Term Dietary Consumption of Grapes Alters Phenotypic Expression in Skeletal Muscle of Aged Male and Female Mice.Foods (Basel, Switzerland) · 2025Article
- Amplification is the primary mode of gene-by-sex interaction in complex human traits.Cell genomics · 2023Article
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Authors and funding
3 authors at 1 institution in 1 country.
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Abstract
Phenotypic differences across sexes are pervasive, but the genetic architecture of sex differences within and across phenotypes is mostly unknown. In this study, we aimed to improve detection power for sex-differentially contributing SNPs previously demonstrated to be enriched in disease association, and we investigate their functions in health, pathophysiology, and genetic function. We leveraged GIANT and UK Biobank summary statistics and defined a set of 2,320 independent SNPs having sexually dimorphic effects within and across biometric traits (MAF > 0.001, P < 5x10-8). Biometric trait sex-heterogeneous SNPs (sex-het SNPs) showed enrichment in association signals for 20 out of 33 diseases/traits at 5% alpha compared to sex-homogeneous matched SNPs (empP < 0.001), and were significantly overrepresented in muscle, skeletal and stem cell development processes, and in calcium channel and microtubule complexes (FDR < 0.05, empP < 0.05). Interestingly, we found that sex-het SNPs significantly map to predicted expression quantitative trait loci (Pr-eQTLs) across brain and other tissues, methylation quantitative trait loci (meQTLs) during development, and transcription start sites, compared to sex-homogeneous SNPs. Finally, we verified that the sex-het disease/trait enrichment was not explained by Pr-eQTL enrichment alone, as sex-het Pr-eQTLs were more enriched than matched sex-homogeneous Pr-eQTLs. We conclude that genetic polymorphisms with sexually dimorphic effects on biometric traits not only contribute to fundamental embryogenic processes, but later in life play an outsized role in disease risk. These sex-het SNPs disproportionately influence gene expression and have a greater influence on disorders of body and brain than other expression-regulatory variation. Together, our data emphasize the genetic underpinnings of sexual dimorphism and its role in human health.
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