A genome-wide case-only test for the detection of digenic inheritance in human exomes

Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19367-19375. doi: 10.1073/pnas.1920650117. Epub 2020 Jul 27.

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.

Keywords: case-only; craniosynostosis; digenic inheritance; genome-wide; next-generation sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Craniosynostoses / genetics
  • Epistasis, Genetic
  • Exome / genetics
  • Exome Sequencing / methods*
  • Genetic Linkage
  • Genetic Variation
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Models, Genetic
  • Multifactorial Inheritance*