Abstract HUP1: Neighborhood Deprivation And Polygenic Contribution To Acute Ischemic Stroke: Results From The All Of Us Research Program

Background: The interaction between social determinants of health and genetic risk factors in causing acute ischemic stroke (AIS) is poorly understood. We hypothesize that community deprivation, a geographic metric that captures several social determinants of health, modifies the effect of genetic variation on risk of AIS. Methods: We analyzed data from All of Us , a large population study that aims to enroll one million Americans. We ascertained AIS cases using Observational Medical Outcomes Partnership codes. We evaluated community deprivation using the deprivation index, an aggregate variable derived from six metrics of the American Community Survey that was divided into tertiles. We modeled the polygenic contribution to AIS through a polygenic risk score that included 530 known genetic risk variants for cardiometabolic risk factors. We used multivariable logistic regression to model AIS risk as a function of community deprivation and polygenic risk, using product terms to test for interaction. Results: Out of 372,397 participants currently enrolled in All of Us , 147,492 had available genetic and deprivation index data, including 3,201 (2.2%) strokes. Both community deprivation and the polygenic risk score were independently associated with AIS risk (both p<0.05). We found a significant interaction between community deprivation and polygenic risk (interaction p=0.02, Figure): the polygenic risk score was significantly associated with AIS risk in areas with low community deprivation (OR 1.08, 95%CI 1.02-1.15; p=0.01) but was not associated with this risk in areas of intermediate and high deprivation (both p>0.05). Conclusion: Among study participants enrolled in All of Us, those living in areas of low community deprivation were more susceptible to the effects of polygenic variation. We speculate that in areas with high deprivation, several social determinants of health known to lead to higher risk of AIS dilute the contribution of genetic risk factors.