PROJECT SUMMARY The goal of this proposal is to characterize and quantify the impact of (a) sex, (b) gender-related exposures, and (c) their interactions on heritable disease across the entire medical phenome. The growing availability of large-scale biobanks with electronic health records (EHRs) linked to biospecimens has created a powerful, but still relatively untapped, opportunity for research aimed at understanding the impact of sex and gender-related exposures on human health. The National Human Genome Research Institute (NHGRI) organized the Electronic Medical Records and Genomics (eMERGE) network which brought together investigators around the U.S. to facilitate EHR-based genomic research and the implementation of genomic medicine. We have created a new collaborative between two of the original eMERGE centers that leverages the resources and existing infrastructure at each site including a combined total of over 9 million patient records and over 100,000 genotyped samples linked to EHRs. Large patient cohorts like the Vanderbilt and Northwestern populations are critical resources that enable research on sex and gender-related exposures and their interaction at scale across the clinical phenome. Our preliminary data demonstrates that sex and gender-related exposures including socioeconomic position and sexual assualt trauma can be mined from the medical record. Moreover, we show that these factors are significantly associated with ~30% of the medical phenome. Finally, we provide evidence that sex and gender-related exposures also moderate genetic risk for complex disease. These findings lead to our central hypothesis that sex and gender-associated exposures interact to modify risk for heritable complex diseases. Building on this preliminary data, our first Aim is to identify and validate the effects of sex and gender-related exposures across the clinical phenome. In Aim 2 we employ a genetic epidemiology approach to identify sex-differences in the genetic architecture of 1,051 clinically utilized laboratory tests. Finally, in Aim 3 we bring these two lines of inquiry together to test whether the clinical manifestations of polygenic risk scores (PRS) are modified by sex and gender-related exposures. The proposed research includes both quantitative and qualitative analyses aimed at investigating the genetic, clinical, and psychosocial risk factors that contribute to the development of complex disease in extremely large samples with phenome-wide data and linked genotypes. These sex-aware analyses can be thought of as essential, but currently missing, pieces of the precision approach to medicine.