ArticleNature genetics2018
Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk.
Article in Nature genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 1 of them a synthesis that pooled it.
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Who cites it
130 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.Frontiers of medicine · 2021Pooled it
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- Revisiting retinal and macular degeneration in the genomics era.Nature reviews. Genetics · 2026Review
- The new frontier of newborn screening: integrating genomics, metabolomics, and data science for inborn errors of metabolism.Orphanet journal of rare diseases · 2026Review
- Advancing risk gene discovery across the allele frequency spectrum.HGG advances · 2026Review
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- LongAllele: a joint inference framework for allele-specific analysis on long-read bulk and single-cell RNA sequencing.bioRxiv : the preprint server for biology · 2026Article
- A comparative survey of functional evidence use in hearing and vision loss genetics.Communications medicine · 2026Article
- Paired DNA and RNA sequencing uncovers common and rare variation regulating human retinal gene expression.Nature communications · 2026Article
- Deep learning-based stratification of Schizophrenia Spectrum Disorder from real-world data reveals distinct profiles of common and rare variant genetic signal.medRxiv : the preprint server for health sciences · 2026Article
- Novel LHX8 variants associated with distinctive oocyte morphological abnormalities and maturation arrest in primary infertility.Journal of ovarian research · 2026Article
- Nonlinear transcriptional responses to gradual modulation of transcription factor dosage.eLife · 2026Article
- Monogenic disorders of immunity: Common variants are not so rare.Cell genomics · 2026Review
- High-resolution promoter interaction analysis implicates genes involved in the activation of Type 3 Innate Lymphoid Cells in autoimmune disease risk.bioRxiv : the preprint server for biology · 2026Article
- Interpreting the functional impact of genetic variants: The need for context qualifiers.American journal of human genetics · 2026Review
- Bidirectional causal relationship between rheumatoid arthritis and systemic lupus erythematosus: a Mendelian randomization study.American journal of translational research · 2026Article
- Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.Frontiers in genetics · 2026Review
- Article
- Gain of Alternative Allele Expression of LINC02449 at rs149707223 in Schizophrenia and Bipolar Disorder: Inducing Synaptic Transmission and Behavioral Deficits in Mice.Nature communications · 2025Article
- Revisiting the Genetics of Hypophosphatasia.Journal of inherited metabolic disease · 2025Review
70 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.