Abstract
SummaryFamily-based sequencing studies enable researchers to identify highly penetrant genetic variants too rare to be tested in conventional case-control studies, by studying co-segregation of variant and disease phenotypes. When multiple affected subjects in a family are sequenced, the probability that a variant or a set of variants is shared identical-by-descent by some or all affected relatives provides evidence against the null hypothesis of complete absence of linkage and association. The Rare Variant Sharing software package RVS implements a suite of tools to assess association and linkage between rare genetic variants and a dichotomous disease indicator in family pedigrees.Availability and ImplementationRVS is available as open source software from the Bioconductor webpage at https://bioconductor.org/packages/release/bioc/html/RVS.html.Supplementary information Supplementary data are available at Bioinformatics online.
Highlights
Sequencing distant relatives is an established approach to identify causal variants in Mendelian disorders, but is increasingly applied to identify genetic risk variants in complex disorders
When several affected subjects per family are sequenced, evidence that a rare variant may be causal can be quantified from the probability of sharing alleles by all affected relatives given it was seen in any one family member under the null hypothesis of complete absence of linkage and association
We presented a general framework for calculating such sharing probabilities when two or more affected subjects per family are sequenced, and show how information from multiple families can be combined by calculating a P-value as the sum of the probabilities of sharing events at least as extreme (Bureau et al, 2014a)
Summary
Sequencing distant relatives is an established approach to identify causal variants in Mendelian disorders, but is increasingly applied to identify genetic risk variants in complex disorders. We recently devised a statistical framework for such a setting, based on the notion that sequencing DNA in extended multiplex families can help to identify such high penetrance disease variants too rare in the population to be detected through tests of association in population-based studies (Bureau et al, 2014a). We presented a general framework for calculating such sharing probabilities when two or more affected subjects per family are sequenced, and show how information from multiple families can be combined by calculating a P-value as the sum of the probabilities of sharing events at least as extreme (Bureau et al, 2014a). Sequencing three affected second cousins from a family with multiple oral cleft cases, we successfully employed this approach to identify a causal nonsense mutation in the gene CDH1 (Bureau et al, 2014b). Generations), only affected subjects are sequenced, and estimates of population variant frequencies are not required (Supplementary Material)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
