COBT: a gene-based rare variant burden test for case-only study designs using aggregated genotypes from public reference cohorts

Abstract Rare disease gene discovery is limited by small cohorts and the frequent absence of matched controls. We present the Case-Only Burden Test (COBT), a gene-based burden test for case-only designs accounting for multiple variants per individual and additive effects. COBT uses a Poisson model to test for excess variants in a gene relative to expectations from population mutation rates. Simulations show high power and competitive performance versus case-control burden tests. Validation on 1000 Genomes data demonstrated good model fit and low false-positive rates. Applied to 478 ciliopathy patients, COBT re-identified known causal genes and highlighted candidate variants in unsolved cases.