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bioRxiv · 10.1101/2023.08.14.553248

A Weights-based variant ranking pipeline for familial complex disorders

Ralli, S.·Vira, T.·Robles-Espinoza, C. D.·Adams, D. J.·Brooks-Wilson, A. R.
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Abstract

Identifying genetic susceptibility factors for complex disorders remains a challenging task. We have developed a weights-based pipeline to prioritize variants and genes in collections of small and large pedigrees where genetic heterogeneity is likely, but biological commonalities are plausible. 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 to 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.

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Ralli, S., Vira, T., Robles-Espinoza, C. D., Adams, D. J., Brooks-Wilson, A. R.. 2023-08-16. A Weights-based variant ranking pipeline for familial complex disorders. https://doi.org/10.1101/2023.08.14.553248

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