ArticleProceedings of the National Academy of Sciences of the United States of America2020
A genome-wide case-only test for the detection of digenic inheritance in human exomes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed.
- Population-specific rare variants influence age at diagnosis in Korean inflammatory bowel disease.The Korean journal of internal medicine · 2026Article
- Co-occurrence of rare variants implicates gene pairs in cytoskeletal pathways and is associated with increased severity in autism spectrum disorder.Genome biology · 2026Article
- The oligogenic inheritance test GCOD detects risk genes and their interactions in congenital heart defects.Genome research · 2026Article
- Benchmark of computational methods to detect digenism in sequencing data.European journal of human genetics : EJHG · 2025Review
- Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data.American journal of human genetics · 2025Article
- Whole exome sequencing identifies concurrentFrontiers in genetics · 2025Article
- Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency.International journal of molecular sciences · 2024Review
- Digenic Inheritance in Rare Disorders and Mitochondrial Disease-Crossing the Frontier to a More Comprehensive Understanding of Etiology.International journal of molecular sciences · 2024Review
- Interferon-Science (New York, N.Y.) · 2024Review
- Decoding mutational hotspots in human disease through the gene modules governing thymic regulatory T cells.Frontiers in immunology · 2024Article
- The Power of Clinical Diagnosis for Deciphering Complex Genetic Mechanisms in Rare Diseases.Genes · 2023Review
- Overview of frequent pattern mining.Genomics & informatics · 2022Article
- A general framework for identifying oligogenic combinations of rare variants in complex disorders.Genome research · 2022Article
- Centers for Mendelian Genomics: A decade of facilitating gene discovery.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Review
- Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy.Journal of personalized medicine · 2022Review
- A computational approach for detecting physiological homogeneity in the midst of genetic heterogeneity.American journal of human genetics · 2021Article
- The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases.Molecular systems biology · 2020Article
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9 authors.
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Abstract
Whole-exome sequencing (WES) has facilitated the discovery of genetic lesions underlying monogenic disorders. Incomplete penetrance and variable expressivity suggest a contribution of additional genetic lesions to clinical manifestations and outcome. Some monogenic disorders may therefore actually be digenic. However, only a few digenic disorders have been reported, all discovered by candidate gene approaches applied to at least one locus. We propose here a two-locus genome-wide test for detecting digenic inheritance in WES data. This approach uses the gene as the unit of analysis and tests all pairs of genes to detect pairwise gene × gene interactions underlying disease. It is a case-only method, which has several advantages over classic case-control tests, in particular by avoiding recruitment of controls. Our simulation studies based on real WES data identified two major sources of type I error inflation in this case-only test: linkage disequilibrium and population stratification. Both were corrected by specific procedures. Moreover, our case-only approach is more powerful than the corresponding case-control test for detecting digenic interactions in various population stratification scenarios. Finally, we confirmed the potential of our unbiased, genome-wide approach by successfully identifying a previously reported digenic lesion in patients with craniosynostosis. Our case-only test is a powerful and timely tool for detecting digenic inheritance in WES data from patients.
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