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A network-based method for associating genes with autism spectrum disorder.

ABSTRACT: Autism spectrum disorder (ASD) is a highly heritable complex disease that affects 1% of the population, yet its underlying molecular mechanisms are largely unknown. Here we study the problem of predicting causal genes for ASD by combining genome-scale data with a network propagation approach. We construct a predictor that integrates multiple omic data sets that assess genomic, transcriptomic, proteomic, and phosphoproteomic associations with ASD. In cross validation our predictor yields mean area under the ROC curve of 0.87 and area under the precision-recall curve of 0.89. We further show that it outperforms previous gene-level predictors of autism association. Finally, we show that we can use the model to predict genes associated with Schizophrenia which is known to share genetic components with ASD.

SUBMITTER: Zadok N

PROVIDER: S-EPMC10960359 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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A network-based method for associating genes with autism spectrum disorder.

Zadok Neta N Ast Gil G Sharan Roded R

Frontiers in bioinformatics 20240308

Autism spectrum disorder (ASD) is a highly heritable complex disease that affects 1% of the population, yet its underlying molecular mechanisms are largely unknown. Here we study the problem of predicting causal genes for ASD by combining genome-scale data with a network propagation approach. We construct a predictor that integrates multiple omic data sets that assess genomic, transcriptomic, proteomic, and phosphoproteomic associations with ASD. In cross validation our predictor yields mean are ...[more]

PMID: 38525240

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Project description:BackgroundAutism is a neurodevelopmental disorder that is usually diagnosed in early childhood. Timely diagnosis and early initiation of treatments such as behavioral therapy are important in autistic people. Discovering critical genes and regulators in this disorder can lead to early diagnosis. Since the contribution of miRNAs along their targets can lead us to a better understanding of autism, we propose a framework containing two steps for gene and miRNA discovery.MethodsThe first step, called the FA_gene algorithm, finds a small set of genes involved in autism. This algorithm uses the WGCNA package to construct a co-expression network for control samples and seek modules of genes that are not reproducible in the corresponding co-expression network for autistic samples. Then, the protein-protein interaction network is constructed for genes in the non-reproducible modules and a small set of genes that may have potential roles in autism is selected based on this network. The second step, named the DMN_miRNA algorithm, detects the minimum number of miRNAs related to autism. To do this, DMN_miRNA defines an extended Set Cover algorithm over the mRNA-miRNA network, consisting of the selected genes and corresponding miRNA regulators.ResultsIn the first step of the framework, the FA_gene algorithm finds a set of important genes; TP53, TNF, MAPK3, ACTB, TLR7, LCK, RAC2, EEF2, CAT, ZAP70, CD19, RPLP0, CDKN1A, CCL2, CDK4, CCL5, CTSD, CD4, RACK1, CD74; using co-expression and protein-protein interaction networks. In the second step, the DMN_miRNA algorithm extracts critical miRNAs, hsa-mir-155-5p, hsa-mir-17-5p, hsa-mir-181a-5p, hsa-mir-18a-5p, and hsa-mir-92a-1-5p, as signature regulators for autism using important genes and mRNA-miRNA network. The importance of these key genes and miRNAs is confirmed by previous studies and enrichment analysis.ConclusionThis study suggests FA_gene and DMN_miRNA algorithms for biomarker discovery, which lead us to a list of important players in ASD with potential roles in the nervous system or neurological disorders that can be experimentally investigated as candidates for ASD diagnostic tests.

Dataset Information

A network-based method for associating genes with autism spectrum disorder.

Publications

A network-based method for associating genes with autism spectrum disorder.

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