PROJECT SUMMARY Sex differences in stroke risk over the life course have been well-described, but we lack the knowledge of how to use such differences to personalize stroke prevention and achieve a lower burden of stroke-related death and disability. Our proposed work on the role of sex hormones in stroke risk will not only improve our mechanistic knowledge of sex differences in stroke but will allow us to identify novel sex-specific targets to be used for stroke prediction and prevention. Our overarching objective is to characterize a set of novel phenotypic, genomic, epigenomic, and metabolomic sex hormone-related targets that are causally linked to incident stroke using existing epidemiologic cohorts from a diverse population of women and men in the NHLBI Trans-Omics for Precision Medicine (TOPMed) consortium and to then integrate these variables into sex- specific stroke risk scores for validation in an external cohort from ELSA-Brasil. Our team of cerebrovascular, cardiovascular, and genetic epidemiologists along with stroke clinicians, biostatisticians, and sex and gender science experts plan to use existing epidemiologic cohorts within the TOPMed omics consortium to identify the mechanisms underlying sex hormones and stroke and to develop sex-specific prediction models. First, using a targeted genomic approach based on our group’s prior work, we will elucidate the role of sex hormones (including sex hormone binding globulin, SHBG) in the etiology of stroke risk. To achieve this, we will use single nucleotide polymorphisms (SNPs) and genetic targets informed by our prior work to conduct sex- disaggregated mendelian randomization analyses of the relationship between sex hormone levels and incident stroke. Secondly, in an integrative omics analysis, we will elucidate sex hormone related biologic mechanistic pathways for risk of incident stroke. Using existing TOPMed omics data, we will identify DNA methylation and metabolomic profiles linking genetic determinants of hormone levels (individual SNPs and a hormone-based genetic risk score) and physiologic variations in measured sex hormone levels to stroke risk in a series of sex- disaggregated mediation analyses. Finally, we will develop novel, sex-specific stroke prediction models in TOPMed incorporating sex hormone-based genetic risk scores, sex hormone levels, the presence of particular methylation and metabolomic profiles, and the presence of established clinical, lifestyle, and reproductive risk factors. We will then validate the models in a nested case cohort ancillary study of participants from ELSA- Brasil. In summary, we propose to use existing prospective cohort studies with an integrative omics approach to understand the relationship between endogenous sex hormones and stroke risk, a needed step toward the use of biologic sex to achieve personalized stroke prevention. Finding evidence to support biologic mechanisms underlying the relationship between sex hormones and stroke could help to establish causality, improve risk prediction, and identify novel targets for improved, more personalized, stroke prevention and improved brain health.

PROJECT NARRATIVE Stroke is a leading cause of death and disability globally and in the United States for both women and men, and sex differences in both risk factors and stroke incidence have been consistently demonstrated. We lack, however, a detailed understanding of pathways by which alterations in sex hormones contribute to stroke risk in women and men, knowledge that could help to inform improved, more personalized stroke prediction and prevention. Our planned project will use the biologic footprints (genomic, epigenomic, and metabolomic data) of individuals in national and international prospective cohort studies to advance our knowledge of the critical role of sex hormones in stroke risk in women and men across the lifespan, enabling more personalized approaches to stroke prevention and improved brain health in the population.