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Protein Interaction Networks Reveal Novel Autism Risk Genes within GWAS Statistical Noise

2014-11-19Journal article Open access
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dc.contributor.authorCorreia, C.
dc.contributor.authorOliveira, G.
dc.contributor.authorVicente, A.M.
dc.date.accessioned2014-11-26T17:21:20Z
dc.date.available2014-11-26T17:21:20Z
dc.date.issued2014-11-19
dc.description.abstractGenome-wide association studies (GWAS) for Autism Spectrum Disorder (ASD) thus far met limited success in the identification of common risk variants, consistent with the notion that variants with small individual effects cannot be detected individually in single SNP analysis. To further capture disease risk gene information from ASD association studies, we applied a network-based strategy to the Autism Genome Project (AGP) and the Autism Genetics Resource Exchange GWAS datasets, combining family-based association data with Human Protein-Protein interaction (PPI) data. Our analysis showed that autism-associated proteins at higher than conventional levels of significance (P<0.1) directly interact more than random expectation and are involved in a limited number of interconnected biological processes, indicating that they are functionally related. The functionally coherent networks generated by this approach contain ASD-relevant disease biology, as demonstrated by an improved positive predictive value and sensitivity in retrieving known ASD candidate genes relative to the top associated genes from either GWAS, as well as a higher gene overlap between the two ASD datasets. Analysis of the intersection between the networks obtained from the two ASD GWAS and six unrelated disease datasets identified fourteen genes exclusively present in the ASD networks. These are mostly novel genes involved in abnormal nervous system phenotypes in animal models, and in fundamental biological processes previously implicated in ASD, such as axon guidance, cell adhesion or cytoskeleton organization. Overall, our results highlighted novel susceptibility genes previously hidden within GWAS statistical "noise" that warrant further analysis for causal variants.por
dc.identifier.citationPLoS One. 2014 Nov 19;9(11):e112399. doi: 10.1371/journal.pone.0112399. eCollection 2014.por
dc.identifier.doi10.1371/journal.pone.011239
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.18/2466
dc.language.isoengpor
dc.publisherPublic Library of Sciencepor
dc.relation.publisherversionhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0112399por
dc.subjectPerturbações do Desenvolvimento Infantil e Saúde Mentalpor
dc.subjectAutismpor
dc.subjectSaúde Públicapor
dc.subjectPortugalpor
dc.titleProtein Interaction Networks Reveal Novel Autism Risk Genes within GWAS Statistical Noisepor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlacePLoS ONEpor
oaire.citation.endPagee112399por
oaire.citation.startPagee112399por
oaire.citation.volume9(11)por
rcaap.rightsopenAccesspor
rcaap.typearticlepor

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