Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

Heart disease is a leading cause of disability and death in Canada. A predisposition to disease of the heart muscle, cardiomyopathy (CM), can be caused by deleterious variations in a single gene ("monogenic disease"). Monogenic CM can lead to young onset of heart disease and higher risk of major life-threatening outcomes, such as sudden cardiac death. There are well-documented differences in the time to diagnosis, time to specialist care, and outcomes biased against women and non-White populations. Specialized computer tools can estimate if someone has a predicted deleterious genetic variant (PDV) in a gene known to cause monogenic disease. However, these tools are less likely to classify PDVs as disease-causing in diverse populations due to historical underrepresentation of non-White populations in reference databases used by these tools. Further, there are biological sex differences in how a CM PDV may manifest in disease between males and females. Intersectional analyses of population PDV burden and outcomes by both race/ancestry and sex/gender are lacking. This research aims to examine the frequency of PDV evidence of monogenic CM and other heart disease risk factors and outcomes in the AllOfUs biobank. AllOfUs is the largest and most diverse dataset available to researchers large enough to do these analyses. This research aims to investigate differences in rates of PDV classifications and genetic diagnoses in participants with CM by race/ancestry and outcomes by gender/sex. Further, we will explore the prevalence of PDVs, CM and outcomes in participants with PDVs in ANK2, a strong novel gene candidate for CM gene-disease association enriched in a Canadian Indigenous population. The findings of this study will directly influence clinical guidelines for determining which patients with CM should undergo genetic testing, while highlighting measurable targets for reduction of inequity in precision medicine.