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Nat Genet. 2018 Sep;50(9):1327-1334. doi: 10.1038/s41588-018-0192-y. Epub 2018 Aug 20.

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

Author information

1
New York Genome Center, New York, NY, USA. scastel@nygenome.org.
2
Department of Systems Biology, Columbia University, New York, NY, USA. scastel@nygenome.org.
3
New York Genome Center, New York, NY, USA.
4
Research Programs Unit, Genome-Scale Biology & Medicine, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
5
Department of Systems Biology, Columbia University, New York, NY, USA.
6
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
7
The Scripps Translational Science Institute, La Jolla, CA, USA.
8
Broad Institute of MIT and Harvard, Cambridge, USA.
9
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
10
Universitat Pompeu Fabrea (UPF), Barcelona, Spain.
11
Cold Spring Harbor Laboratory, New York, NY, USA.
12
New York Genome Center, New York, NY, USA. tlappalainen@nygenome.org.
13
Department of Systems Biology, Columbia University, New York, NY, USA. tlappalainen@nygenome.org.

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. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.

PMID:
30127527
PMCID:
PMC6119105
[Available on 2019-02-20]
DOI:
10.1038/s41588-018-0192-y

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