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Game theoretic centrality: a novel approach to prioritize disease candidate genes by combining biological networks with the Shapley value

Sun, Min Woo; Moretti, Stefano; Paskov, Kelley; Stockham, Nate; Varma, Maya; Chrisman, Brianna; Washington, Peter Y.; Jung, Jae-Yoon; Wall, Dennis P. (2020), Game theoretic centrality: a novel approach to prioritize disease candidate genes by combining biological networks with the Shapley value, BMC Bioinformatics, 21, 1. 10.1186/s12859-020-03693-1

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Game_theoretic.pdf (2.022Mb)
Type
Article accepté pour publication ou publié
Date
2020
Journal name
BMC Bioinformatics
Volume
21
Number
1
Publisher
BioMed Central
Publication identifier
10.1186/s12859-020-03693-1
Metadata
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Author(s)
Sun, Min Woo
Moretti, Stefano
Laboratoire d'analyse et modélisation de systèmes pour l'aide à la décision [LAMSADE]
Paskov, Kelley
Stockham, Nate
Varma, Maya
Chrisman, Brianna
Washington, Peter Y.
Jung, Jae-Yoon
Wall, Dennis P.
Abstract (EN)
Background: Complex human health conditions with etiological heterogeneity like Autism Spectrum Disorder (ASD) often pose a challenge for traditional genome-wide association study approaches in defining a clear genotype to phenotype model. Coalitional game theory (CGT) is an exciting method that can consider the combinatorial effect of groups of variants working in concert to produce a phenotype. CGT has been applied to associate likely-gene-disrupting variants encoded from whole genome sequence data to ASD; however, this previous approach cannot take into account for prior biological knowledge. Here we extend CGT to incorporate a priori knowledge from biological networks through a game theoretic centrality measure based on Shapley value to rank genes by their relevance-the individual gene's synergistic influence in a gene-to-gene interaction network. Game theoretic centrality extends the notion of Shapley value to the evaluation of a gene's contribution to the overall connectivity of its corresponding node in a biological network. Results: We implemented and applied game theoretic centrality to rank genes on whole genomes from 756 multiplex autism families. Top ranking genes with the highest game theoretic centrality in both the weighted and unweighted approaches were enriched for pathways previously associated with autism, including pathways of the immune system. Four of the selected genes HLA-A, HLA-B, HLA-G, and HLA-DRB1-have also been implicated in ASD and further support the link between ASD and the human leukocyte antigen complex. Conclusions: Game theoretic centrality can prioritize influential, disease-associated genes within biological networks, and assist in the decoding of polygenic associations to complex disorders like autism.
Subjects / Keywords
Coalitional game theory; Biological network; Shapley value; Game theoretic centrality; Autism spectrum disorder

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