Research Questions:
Sex differences in health and disease are well recognized, yet most studies focus only on mean differences between males and females. Much less is known about sex differences in phenotypic variability, despite growing evidence that this variability may underlie differential disease risk and treatment response. Our recent work identified sex-differentially variable (SDV) genes-genes whose expression variability differs between sexes-implicating pathways related to immune function, hormone signaling, and cellular regulation. Importantly, we found an enrichment of Graves’ disease-associated genes among those with greater variability in females, suggesting a mechanistic link to sex-biased autoimmune disease.
Objecctives:
The proposed project will use the UK Biobank to investigate the genetic basis and health impact of SDV genes. Specifically, we will: (1) identify genetic variants (QTLs) contributing to sex-specific gene expression variability; (2) assess the association of SDV genes and variants with sex-biased diseases such as Graves’ disease and rheumatoid arthritis using GWAS and PheWAS; (3) evaluate evolutionary signatures (e.g., nucleotide diversity, Fst) to understand population-level differences; and (4) develop polygenic scores stratified by sex to clarify the contribution of SDV genes to disease risk prediction. Together, these analyses will provide new insights into why men and women experience different disease risks and outcomes.
Scientific rationales:
This research is directly relevant to public health, as sex-biased diseases impose major clinical and economic burdens. By uncovering genetic mechanisms that drive sex differences in disease, our findings may inform risk prediction, prevention, and precision medicine approaches. Results will be disseminated through peer-reviewed publications, conference presentations, and open-access resources, ensuring accessibility to the scientific community and the public.
