Dataset Information

Coalitional Game Theory Facilitates Identification of Non-Coding Variants Associated With Autism.

ABSTRACT: Studies on autism spectrum disorder (ASD) have amassed substantial evidence for the role of genetics in the disease's phenotypic manifestation. A large number of coding and non-coding variants with low penetrance likely act in a combinatorial manner to explain the variable forms of ASD. However, many of these combined interactions, both additive and epistatic, remain undefined. Coalitional game theory (CGT) is an approach that seeks to identify players (individual genetic variants or genes) who tend to improve the performance-association to a disease phenotype of interest-of any coalition (subset of co-occurring genetic variants) they join. This method has been previously applied to boost biologically informative signal from gene expression data and exome sequencing data but remains to be explored in the context of cooperativity among non-coding genomic regions. We describe our extension of previous work, highlighting non-coding chromosomal regions relevant to ASD using CGT on alteration data of 4595 fully sequenced genomes from 756 multiplex families. Genomes were encoded into binary matrices for three types of non-coding regions previously implicated in ASD and separated into ASD (case) and unaffected (control) samples. A player metric, the Shapley value, enabled determination of individual variant contributions in both sets of cohorts. A total of 30 non-coding positions were found to have significantly elevated player scores and likely represent significant contributors to the genetic coordination underlying ASD. Cross-study analyses revealed that a subset of mutated non-coding regions (all of which are in human accelerated regions (HARs)) and related genes are involved in biological pathways or behavioral outcomes known to be affected in autism, suggesting the importance of single nucleotide polymorphisms (SNPs) within HARs in ASD. These findings support the use of CGT in identifying hidden yet influential non-coding players from large-scale genomic data, to better understand the precise underpinnings of complex neurodevelopmental disorders such as autism.

SUBMITTER: Sun MW

PROVIDER: S-EPMC6410388 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Coalitional Game Theory Facilitates Identification of Non-Coding Variants Associated With Autism.

Sun Min Woo MW Gupta Anika A Varma Maya M Paskov Kelley M KM Jung Jae-Yoon JY Stockham Nate T NT Wall Dennis P DP

Biomedical informatics insights 20190308

Studies on autism spectrum disorder (ASD) have amassed substantial evidence for the role of genetics in the disease's phenotypic manifestation. A large number of coding and non-coding variants with low penetrance likely act in a combinatorial manner to explain the variable forms of ASD. However, many of these combined interactions, both additive and epistatic, remain undefined. Coalitional game theory (CGT) is an approach that seeks to identify players (individual genetic variants or genes) who ...[more]

PMID: 30886520

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Project description:Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, we first identified ASD-related lncRNAs based on genomic variant data of individuals with ASD from a twin study. In total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by an independent copy number variant (CNV) dataset. Then, the functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of their three different types of functional neighbor genes (i.e., genomic neighbors, competing endogenous RNA (ceRNA) neighbors, and gene co-expression neighbors in the cortex). The results have shown that most of the functional neighbor genes of ASD-related lncRNAs were enriched in nervous system development, inflammatory responses, and transcriptional regulation. Moreover, we explored the differential functions of ASD-related lncRNAs in distinct brain regions by using gene co-expression network analysis based on tissue-specific gene expression profiles. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. In addition, a functional network analysis was conducted for the highly reliable functional neighbor genes of ASD-related lncRNAs. We found that all the highly reliable functional neighbor genes were connected in a single functional network, which provided additional clues for the action mechanisms of ASD-related lncRNAs. Finally, we predicted several potential drugs based on the enrichment of drug-induced pathway sets in the ASD-altered biological pathway list. Among these drugs, several (e.g., amoxapine, piperine, and diflunisal) were partly supported by the previous reports. In conclusion, ASD-related lncRNAs participated in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. Detailed investigation into ASD-related lncRNAs can provide clues for developing potential ASD diagnosis biomarkers and therapy.

Dataset Information

Coalitional Game Theory Facilitates Identification of Non-Coding Variants Associated With Autism.

Publications

Coalitional Game Theory Facilitates Identification of Non-Coding Variants Associated With Autism.

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