Allelic series are of candidate therapeutic interest because of the existence of a dose-response relationship between the functionality of a gene and the degree or severity of a phenotype. We define a Show more
Allelic series are of candidate therapeutic interest because of the existence of a dose-response relationship between the functionality of a gene and the degree or severity of a phenotype. We define an allelic series as a collection of variants in which increasingly deleterious mutations lead to increasingly large phenotypic effects, and we have developed a gene-based rare-variant association test specifically targeted to identifying genes containing allelic series. Building on the well-known burden test and sequence kernel association test (SKAT), we specify a variety of association models covering different genetic architectures and integrate these into a Coding-Variant Allelic-Series Test (COAST). Through extensive simulations, we confirm that COAST maintains the type I error and improves the power when the pattern of coding-variant effect sizes increases monotonically with mutational severity. We applied COAST to identify allelic-series genes for four circulating-lipid traits and five cell-count traits among 145,735 subjects with available whole-exome sequencing data from the UK Biobank. Compared with optimal SKAT (SKAT-O), COAST identified 29% more Bonferroni-significant associations with circulating-lipid traits, on average, and 82% more with cell-count traits. All of the gene-trait associations identified by COAST have corroborating evidence either from rare-variant associations in the full cohort (Genebass, n = 400,000) or from common-variant associations in the GWAS Catalog. In addition to detecting many gene-trait associations present in Genebass by using only a fraction (36.9%) of the sample, COAST detects associations, such as that between ANGPTL4 and triglycerides, that are absent from Genebass but that have clear common-variant support. Show less
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL Show more
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less