PROJECT SUMMARY Sex differences in human diseases are well-recognized, but the mechanisms are not well understood. This gap of knowledge delays the progress in risk assessment and therapeutic strategies for sex-aware precision healthcare. While studies have shown significant sex differences in the genetic architectures of complex diseases, most investigators opted to do sex- combined analyses in disease genetic studies to maximize statistical power. NIH recently began to reinforce the inclusion of sex as a biological variable in the design, analysis, and reporting of vertebrate animal and human studies. Insights into the functional genetic bases of sex as a biological variable are critical to develop therapeutic interventions that equally benefit each sex. We recently found that ~1% variants in the population have sex-biased allele frequency, including ~10% of disease variants in the Genome Aggregation Database (gnomAD). These variants preferentially occur in tissue-specific sex-differentially expressed genes. We propose a novel approach to study sex differences in disease genetic architectures by leveraging variants that are sex-biased either in allele frequency or phenotypic association. We believe this approach will increase the statistical power to identify sex-specific or sex interacting causal variants in sex- biased diseases. We will identify and characterize sex-biased variants in gnomAD, Genotype- Tissue Expression project (GTEx) and Trans-Omics for Precision Medicine for sleep disordered breathing phenotypes and venous thromboembolism case-control datasets. We will subsequently study the functional mechanisms of these sex-biased variants in ~50 GTEx tissues. The completion of this pilot study will advance future genetic studies of sex-divergent disorders and accelerate the realization of sex-aware genomic medicine.