Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories

Rare variants are collectively numerous and may underlie a considerable proportion of complex disease risk. However, identifying genuine rare variant associations is challenging due to small effect sizes, presence of technical artefacts, and heterogeneity in population structure. We hypothesized that rare variant burden over a large number of genes can be combined into predictive rare variant genetic risk score (RVGRS). We propose a novel method (RV-EXCALIBER) that leverages summary-level data from a large public exome sequencing database (gnomAD) as controls and robustly calibrates rare variant burden to account for the aforementioned biases. A RVGRS was found to strongly associate with coronary artery disease (CAD) in European and South Asian populations. Calibrated RVGRS capture the aggregate effect of rare variants through a polygenic model of inheritance, identifies 1.5% of the population with substantial risk of early CAD, and confers risk even when adjusting for known Mendelian CAD genes, clinical risk factors, and common variant gene scores.