Variant ranking pipeline for complex familial disorders

Abstract

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.

Figure 1

Overview of the weight-based variant ranking pipeline for complex familial disorders. Generated using draw.io (version 21.6.5; https://app.diagrams.net/).

Figure 2

Biological interaction network generated using Cytoscape v3.9.1 for top15 variants from 13 melanoma families. Edges with "⟶" indicate activating/catalyzing, "-|" designates inhibition, "-" specifies FIs extracted from complexes or inputs, and "---" is for predicted Fis in the figure.

Figure 3

Biological commonalities between known germline melanoma genes, and genes somatically mutated in melanomas, and/or genes identified through GWAS of melanoma cases. Generated using Venn Diagrams (https://www.vandepeerlab.org/?q=tools/venn-diagrams).