Social Determinants of Health and Lifestyle Risk Factors Modulate Genetic Susceptibility for Women's Health Outcomes

Women's health conditions are influenced by both genetic and environmental factors. Understanding these factors individually and their interactions is crucial for implementing preventative, personalized medicine. However, since genetics and environmental exposures, particularly social determinants of health (SDoH), are correlated with race and ancestry, risk models without careful consideration of these measures can exacerbate health disparities. We focused on seven women's health disorders in the All of Us Research Program: breast cancer, cervical cancer, endometriosis, ovarian cancer, preeclampsia, uterine cancer, and uterine fibroids. We computed polygenic risk scores (PRSs) from publicly available weights and tested the effect of the PRSs on their respective phenotypes as well as any effects of genetic risk on age at diagnosis. We next tested the effects of environmental risk factors (BMI, lifestyle measures, and SDoH) on age at diagnosis. Finally, we examined the impact of environmental exposures in modulating genetic risk by stratified logistic regressions for different tertiles of the environment variables, comparing the effect size of the PRS. Of the twelve sets of weights for the seven conditions, nine were significantly and positively associated with their respective phenotypes. None of the PRSs was associated with different age at diagnoses in the time-to-event analyses. The highest environmental risk group tended to be diagnosed earlier than the low and medium-risk groups. For example, the cases of breast cancer, ovarian cancer, uterine cancer, and uterine fibroids in highest BMI tertile were diagnosed significantly earlier than the low and medium BMI groups, respectively). PRS regression coefficients were often the largest in the highest environment risk groups, showing increased susceptibility to genetic risk. This study's strengths include the diversity of the All of Us study cohort, the consideration of SDoH themes, and the examination of key risk factors and their interrelationships. These elements collectively underscore the importance of integrating genetic and environmental data to develop more precise risk models, enhance personalized medicine, and ultimately reduce health disparities.