An allelic series rare variant association test for candidate gene discovery

Abstract

Allelic series are of candidate therapeutic interest due to 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 gene in which increasingly deleterious mutations lead to increasingly large phenotypic effects, and develop a gene-based rare variant association test specifically targeted for the identification of allelic series. Building on the well-known burden and sequence kernel association tests (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 power when the pattern of coding-variant effect sizes increases monotonically with mutational severity. We applied COAST to identify allelic series for 4 circulating lipid traits and 5 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 results in the full cohort (Genebass, N=400K), or from common variant results in the GWAS catalog. In addition to detecting many gene-trait associations present in Genebass using only a fraction (36.9%) of the sample, COAST detects associations, such as ANGPTL4 with triglycerides, that are absent from Genebass but which have clear common variant support.

Non-linear transcriptional responses to gradual modulation of transcription factor dosage

“…Cell hashing was performed as previously described using four hashtag-derived oligonucleotides (HTOs) in a hyperconjugation protocol 10 . Each transduced cell line was split into four batches of 500,000 cells, resulting in a total of 8 different hashes.…”

“…However, our understanding of the quantitative relationship between gradual changes of gene dosage and downstream phenotypes remains elusive for most human genes. Practical applications of the compelling allelic series concept to identify genes where increasingly deleterious mutations have increasing phenotypic effects have been limited by the sparsity of segregating variants with an impact on a given gene in the human population 10 . Experimental characterization of gene function in model systems has predominantly relied on gene knock-out or knock-down approaches 11 .…”