Contact PD/PI: Soemedi, Rachel 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. Project Summary/Abstract Page 6

PROJECT NARRATIVE Sex differences in human diseases are common, but they are not well understood. We will establish a novel framework to study the genetic architectures of sex-biased diseases by leveraging variants with sex biased allele frequency or phenotypic association. Understanding the functional genetic bases of sex differences is critical in order to develop effective and safe therapeutic strategies for sex-biased diseases. Project Narrative Page 7