biostudies-literatureKerner GNCATS NIH HHSAgence Nationale de la RechercheNIDDK NIH HHSOffice of Extramural Research, National Institutes of HealthNHGRI NIH HHSHHS | NIH | National Human Genome Research InstituteNational Human Genome Research InstituteNIH HHS19367-19375https://www.ebi.ac.uk/biostudies/studies/S-EPMC7430978biostudies-literatureUnknown117(32)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 recruProceedings of the National Academy of Sciences of the United States of AmericaA genome-wide case-only test for the detection of digenic inheritance in human exomes.PMC7430978ANR-14-CE14- 0007-01ANR-16-CE12-0023-01UL1 TR001866UL1 TR001863S10 OD018521U24 HG008956ANR-10-IAHU-01P30 DK079310UM1HG006504UM1 HG0065048UL1TR001866Bouaziz MCobat AKerner GTimberlake ATCasanova JLAbel LBigio BLifton RPBustamante JfalseA genome-wide case-only test for the detection of digenic inheritance in human exomes.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 recru2020-01-01T00:00:00Z2020 Aug2026-05-03T00:17:20.895Z2021-02-21T03:41:20ZS-EPMC74309783271911210.1073/pnas.1920650117