Precision Contraception: Genetic Variation in Symptom Response to Hormonal Contraceptive Exposure

PROJECT ABSTRACT AND SUMMARY Hormonal contraception (HC) is one of the most widely used medications by individuals assigned female at birth during their reproductive years. Yet, responses to HC are highly variable, leading to side effects that contribute to discontinuation and switching. Despite widespread use, there remains a limited understanding of the biological mechanisms that drive differences in tolerance and symptom burden. This proposal leverages the NIH All of Us Research Program (AoU), which provides a uniquely large and diverse dataset including electronic health records, pharmacy data, survey responses, and genomic information. The central hypothesis is that genetic variants influence individual differences in response to HC and that side effects can be systematically characterized using integrated real-world data. To test this, we propose two aims. Aim 1 will define clinical and genetic correlates of HC side effects through a series of logistic and linear regression analyses linking candidate genetic variants (e.g., CYP3A4, PGR, SHBG, ESR1) to diagnosis codes and symptom profiles among HC users compared to non-users. Aim 2 will perform a phenome-wide association study (PheWAS) to examine associations between candidate single nucleotide polymorphisms (SNPs) and a broad set of phenotypes, stratified by HC exposure status. This dual approach will provide both hypothesis- driven and exploratory insights into the genetic underpinnings of contraceptive response. Innovation lies in integrating multi-modal data at the national scale to move toward precision contraceptive prescribing. Expected outcomes include identification of genetic variants associated with side effect burden, improved understanding of discontinuation patterns, and foundational evidence for tailoring contraceptive counseling and prescribing practices. The impact of this work is significant, as it addresses a major gap in reproductive healthcare by providing the first large-scale evidence base for genetic and clinical predictors of HC response, aligning directly with Eunice Kennedy Shriver National Institute of Child Health and Human Development priorities and the All of Us Scientific Roadmap. Findings will inform future efforts to reduce trial-and-error in contraceptive prescribing, improve patient experiences, and enhance long-term reproductive health outcomes.