PT  - JOURNAL ARTICLE
AU  - Stephane E. Castel
AU  - Alejandra Cervera
AU  - Pejman Mohammadi
AU  - François Agut
AU  - Ferran Reverter
AU  - Aaron Wolman
AU  - Roderic Guigo
AU  - Ana Vasileva
AU  - Tuuli Lappalainen
TI  - Modified penetrance of coding variants by <em>cis</em>-regulatory variation shapes human traits
AID  - 10.1101/190397
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 190397
4099  - http://biorxiv.org/content/early/2017/09/18/190397.short
4100  - http://biorxiv.org/content/early/2017/09/18/190397.full
AB  - Coding variants represent many of the strongest associations between genotype and phenotype, however they exhibit inter-individual differences in effect, known as variable penetrance. In this work, we study how cis-regulatory variation modifies the penetrance of coding variants in their target gene. Using functional genomic and genetic data from GTEx, we observed that in the general population, purifying selection has reduced haplotype combinations that lead to higher penetrance of pathogenic coding variants. Conversely, in the germline genomes of individuals with cancer, we observed an increase in predicted penetrance of pathogenic coding variants in disease relevant genes. Finally, we experimentally demonstrated that a regulatory variant can modify the penetrance of a coding variant by introducing a Mendelian SNP using CRISPR-Cas9 on distinct expression haplotypes and using the transcriptome as a phenotypic readout. Our results demonstrate that joint effects of regulatory and coding variants are an important part of the genetic architecture of human traits, and contribute to modified penetrance of disease-causing variants.