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dc.contributor.authorChen, S.en_US
dc.contributor.authorWang, J.en_US
dc.contributor.authorÇiçek, Ercümenten_US
dc.contributor.authorRoeder, K.en_US
dc.contributor.authorYu, H.en_US
dc.contributor.authorDevlin, B.en_US
dc.date.accessioned2021-03-01T11:23:04Z
dc.date.available2021-03-01T11:23:04Z
dc.date.issued2020
dc.identifier.issn2040-2392
dc.identifier.urihttp://hdl.handle.net/11693/75663
dc.description.abstractBackground: Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses. Methods: Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein–protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an “ASD disrupted network.” Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner. Results: Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types—excitatory, inhibitory, and neural progenitor—we implicate several hundred genes in risk (FDR ≤≤0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system. Limitations: Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional. Conclusions: Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD.en_US
dc.language.isoEnglishen_US
dc.source.titleMolecular Autismen_US
dc.relation.isversionofhttps://dx.doi.org/10.1186/s13229-020-00386-7en_US
dc.subjectAutism spectrum disorderen_US
dc.subjectDe novo missense variationen_US
dc.subjectProtein–protein interactionen_US
dc.subjectCell-type-specific transcriptomeen_US
dc.titleDe novo missense variants disrupting protein–protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell typesen_US
dc.typeArticleen_US
dc.departmentDepartment of Computer Engineeringen_US
dc.citation.spage1en_US
dc.citation.epage16en_US
dc.citation.volumeNumber11en_US
dc.citation.issueNumber1en_US
dc.identifier.doi10.1186/s13229-020-00386-7en_US
dc.publisherBioMed Centralen_US
dc.contributor.bilkentauthorÇiçek, Ercüment


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