Rxivist logo

Modified penetrance of coding variants by cis-regulatory variation shapes human traits

By Stephane E. Castel, Alejandra Cervera, Pejman Mohammadi, Fran├žois Aguet, Ferran Reverter, Aaron Wolman, Roderic Guigo, Ivan Iossifov, Ana Vasileva, Tuuli Lappalainen

Posted 18 Sep 2017
bioRxiv DOI: 10.1101/190397 (published DOI: 10.1038/s41588-018-0192-y)

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 depleted haplotype combinations that lead to higher penetrance of pathogenic coding variants. Conversely, in cancer and autism patients, we observed an enrichment of haplotype combinations that lead to higher penetrance of pathogenic coding variants in disease implicated genes, which provides direct evidence that regulatory haplotype configuration of causal coding variants affects disease risk. 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.

Download data

  • Downloaded 3,913 times
  • Download rankings, all-time:
    • Site-wide: 2,103 out of 116,126
    • In genetics: 100 out of 5,126
  • Year to date:
    • Site-wide: 61,149 out of 116,126
  • Since beginning of last month:
    • Site-wide: 62,205 out of 116,126

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)