Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk.

ABSTRACT: Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. F

SUBMITTER: Castel SE 

PROVIDER: S-EPMC6119105 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature