Abstract 13644: Depict Analysis Suggests Enrichment of Heart Valve Tissue Expression in African Rheumatic Heart Disease Patients From the RHDGen GWAS Study Cohort

Introduction: Rheumatic heart disease (RHD) is a sequela of rheumatic fever that results in permanent heart valve damage. While it remains the primary cause of cardiac surgery in Africa, its pathophysiology is poorly understood.Genome-wide association studies (GWASs) are ‘hypothesis-free’, genetic discovery tools for common complex diseases. Recently, our African GWAS of RHD susceptibility uncovered a novel locus (11q24.1; OR=1.63; 95% CI, 1.38-1.94; P=4.36x10 -8 ) which may explain the disproportionate burden in Africans.Here we further report secondary analyses investigating tissue type expression enrichment among suggestively associated loci, to elucidate the underlying biological processes involved in RHD susceptibility. Aims and Objectives: This study sought to identify tissue types enriched in gene-set analyses associated with RHD GWAS susceptibility data in Africans. Methods: A multicenter, ethnically matched case-control GWAS was performed in 2,548 RHD cases and 2,261 controls, from eight African countries. All 4,809 participants were assessed according to the 2012 World Heart Federation (WHF) criteria for echocardiographic diagnosis of RHD. After cleaning, the GWAS data were stratified by ethnicity and an association test was run via mixed linear models in GCTA that adjusted for gender, chip type and the first ten principal components. Using the resulting GWAS summary statistics suggestive loci (P<1x10 -5 ), we conducted secondary analyses in DEPICT (Data-driven Expression Prioritized Integration for Complex Traits) to test for association with RHD and its related traits and tissues, to validate the GWAS findings. Results: DEPICT indicated promising and biologically relevant results; the most enriched tissues were heart valves (p=2.47x10 -3 ; False Discovery Rate (FDR)=<0.20). Discussion and Conclusion: Our results indicate that genetic susceptibility to RHD may involve perturbed gene expression signatures characteristic of heart valves, known for their pathogenic involvement in RHD development. Future larger studies are warranted to identify the specific genes involved.