About: 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 novel 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 and bias 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 validated 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. Significance statement Despite a growing number of reports of rare disorders not fully explained by monogenic lesions, digenic inheritance has been reported for only 54 diseases to date. The very few existing methods for detecting gene x gene interactions from next-generation sequencing data were generally studied in rare-variant association studies with limited simulation analyses for short genomic regions, under a case-control design. We describe the first case-only approach designed specifically to search for digenic inheritance, which avoids recruitment and bias related to controls. We show, through both extensive simulation studies on real WES datasets and application to a real example of craniosynostosis, that our method is robust and powerful for the genome-wide identification of digenic lesions.   Goto Sponge  NotDistinct  Permalink

An Entity of Type : fabio:Abstract, within Data Space : wasabi.inria.fr associated with source document(s)

AttributesValues
type
value
  • 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 novel 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 and bias 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 validated 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. Significance statement Despite a growing number of reports of rare disorders not fully explained by monogenic lesions, digenic inheritance has been reported for only 54 diseases to date. The very few existing methods for detecting gene x gene interactions from next-generation sequencing data were generally studied in rare-variant association studies with limited simulation analyses for short genomic regions, under a case-control design. We describe the first case-only approach designed specifically to search for digenic inheritance, which avoids recruitment and bias related to controls. We show, through both extensive simulation studies on real WES datasets and application to a real example of craniosynostosis, that our method is robust and powerful for the genome-wide identification of digenic lesions.
subject
  • Cloning
  • Genes
  • Transcription factors
  • Bone morphogenetic protein
  • Human proteins
  • Medical genetics
  • Molecular biology
  • Implants (medicine)
  • TGFβ domain
  • Congenital disorders of musculoskeletal system
  • Developmental genes and proteins
  • MH1 domain
  • MH2 domain
part of
is abstract of
is hasSource of
Faceted Search & Find service v1.13.91 as of Mar 24 2020


Alternative Linked Data Documents: Sponger | ODE     Content Formats:       RDF       ODATA       Microdata      About   
This material is Open Knowledge   W3C Semantic Web Technology [RDF Data]
OpenLink Virtuoso version 07.20.3229 as of Jul 10 2020, on Linux (x86_64-pc-linux-gnu), Single-Server Edition (94 GB total memory)
Data on this page belongs to its respective rights holders.
Virtuoso Faceted Browser Copyright © 2009-2025 OpenLink Software