期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 32, 页码 19367-19375出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1920650117
关键词
digenic inheritance; next-generation sequencing; genome-wide; case-only; craniosynostosis
资金
- Institut National de la Sante et de la Recherche Medicale, Paris Descartes University, St. Giles Foundation
- Rockefeller University Center for Clinical and Translational Science grant from the National Center for Research Resources
- National Center for Advancing Translational Sciences of the NIH [8UL1TR001866]
- TBPATHGEN project from the French National Research Agency (ANR) under the Investments for the future program [ANR-14-CE14-0007-01]
- TBPATHGEN project from the French National Research Agency (ANR) under GENMSMD [ANR-16-CE17-0005-01]
- TBPATHGEN project from the French National Research Agency (ANR) under MYCOPARADOX [ANR-16-CE12-0023-01]
- Yale Center for Mendelian Genomics [UM1HG006504]
- National Human Genome Research Institute
- Genome Sequencing Program Coordinating Center [U24 HG008956]
- Institut Imagine (Imagine Thesis Award 2019-2020)
- Agence Nationale de la Recherche (ANR) [ANR-16-CE12-0023] Funding Source: Agence Nationale de la Recherche (ANR)
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 x 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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