Variant ranking pipeline for complex familial disorders.

Autor: Ralli S; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, V5Z 1L3, Canada.; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada., Vira T; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, V5Z 1L3, Canada., Robles-Espinoza CD; Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK., Adams DJ; Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK., Brooks-Wilson AR; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, V5Z 1L3, Canada. arw6@sfu.ca.; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada. arw6@sfu.ca.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jun 13; Vol. 14 (1), pp. 13599. Date of Electronic Publication: 2024 Jun 13.
DOI: 10.1038/s41598-024-64169-3
Abstrakt: Identifying genetic susceptibility factors for complex disorders remains a challenging task. To analyze collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible, we have developed a weights-based pipeline to prioritize variants and genes. The Weights-based vAriant Ranking in Pedigrees (WARP) pipeline prioritizes variants using 5 weights: disease incidence rate, number of cases in a family, genome fraction shared amongst cases in a family, allele frequency and variant deleteriousness. Weights, except for the population allele frequency weight, are normalized between 0 and 1. Weights are combined multiplicatively to produce family-specific-variant weights that are then averaged across all families in which the variant is observed to generate a multifamily weight. Sorting multifamily weights in descending order creates a ranked list of variants and genes for further investigation. WARP was validated using familial melanoma sequence data from the European Genome-phenome Archive. The pipeline identified variation in known germline melanoma genes POT1, MITF and BAP1 in 4 out of 13 families (31%). Analysis of the other 9 families identified several interesting genes, some of which might have a role in melanoma. WARP provides an approach to identify disease predisposing genes in studies with small and large pedigrees.
(© 2024. The Author(s).)
Databáze: MEDLINE
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