Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk
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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.
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Improved recognition of variable penetrance of many monogenic disease alleles has invigorated efforts to identify genetic and environmental modifiers.
“Improved recognition of the variable penetrance of many ‘monogenic’ disease alleles has invigorated efforts to identify the genetic and environmental modifiers responsible26,27.”
From A brief history of human disease genetics (2020) · cites this paper as [27]
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A brief history of human disease genetics
Claussnitzer, M., Cho, J. H., Collins, R., Cox, N. J., Dermitzakis, E. T., Hurles, M. E., Kathiresan, S., Kenny, E. E., Lindgren, C. M., MacArthur, D. G., et al. (2020) · Nature · doi:10.1038/s41586-019-1879-7 · Cited by 697 · see citing works
- Authors
- Castel, S. E., Cervera, A., Mohammadi, P., Aguet, F., Reverter, F., Wolman, A., Guigo, R., Iossifov, I., Vasileva, A., & Lappalainen, T.
- Affiliations
- New York Genome Center (US)
- University of Helsinki (FI)
- Scripps Research Institute (US)
- Broad Institute (US)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Castel, Stephane E.
- Lappalainen, Tuuli
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-08-20
- Volume
- 50
- Issue
- 9
- Pages
- 1327-1334
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6119105
- OpenAlex
- W2885204059
- Cited by
- 217
- References
- 51
- Citations by year
- 2026: 18 · 2025: 19 · 2024: 21 · 2023: 16 · 2022: 33 · 2021: 28 · 2020: 44 · 2019: 31 · 2018: 7
- FWCI
- 16.59
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Simons Foundation
- Simons Foundation Autism Research Initiative
- National Institutes of Health (1k99hg009916-01, HHSN2682010000029C)
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health (R01MH101814, R01MH106842)
- National Institute on Drug Abuse
- National Human Genome Research Institute (UM1HG008901, K99 HG009916)
- NIH Office of the Director (R01MH101814)
- National Cancer Institute
- National Institute of General Medical Sciences (R01GM122924)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK112331)
- National Institute of Neurological Disorders and Stroke
- Common Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- variable penetrance, cis-regulatory variation, coding variants, purifying selection, disease risk, cancer, autism spectrum disorder, single nucleotide polymorphisms, CRISPR/Cas9 genome editing, gene expression, genetic architecture, GTEx
- MeSH terms
- Disease, Haplotypes, Humans, Phenotype, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcriptome, CRISPR-Cas Systems
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