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Identification of neurotransmission and synaptic biological processes Disrupted in Autism Spectrum Disorder using interaction networks and community detection analysis

2023-11-04Artigo científico Acesso aberto
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datacite.subject.fosCiências Sociais::Psicologia
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorVilela, Joana
dc.contributor.authorMartiniano, Hugo
dc.contributor.authorMarques, Ana Rita
dc.contributor.authorSantos, João Xavier
dc.contributor.authorAsif, Muhammad
dc.contributor.authorMaria Rasga, Célia
dc.contributor.authorOliveira, Guiomar
dc.contributor.authorVicente, Astrid Moura
dc.date.accessioned2026-07-07T14:37:10Z
dc.date.available2026-07-07T14:37:10Z
dc.date.issued2023-11-04
dc.description.abstractAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein–protein interactions, and the network’s biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the PDE11A and SYTL3 genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes.eng
dc.description.sponsorshipFundação para a Ciência e Tecnologia - FCT; National Institute of Health Doutor Ricardo Jorge
dc.identifier.citationVilela, J., Martiniano, H., Marques, A. R., Santos, J. X., Asif, M., Rasga, C., Oliveira, G., & Vicente, A. M. (2023). Identification of neurotransmission and synaptic biological processes disrupted in autism spectrum disorder using interaction networks and community detection analysis. Biomedicines, 11(11), 2971. https://doi.org/10.3390/biomedicines11112971
dc.identifier.doi10.3390/biomedicines11112971
dc.identifier.issn2227-9059
dc.identifier.urihttp://hdl.handle.net/10400.12/14021
dc.language.isoeng
dc.peerreviewedyes
dc.publisherMDPI AG
dc.relationUIDB/04046/2020
dc.relationUIDP/04046/2020
dc.relationEXPL/CCI-BIO/0126/2021
dc.relationPD/BD/131390/2017
dc.relation.ispartofBiomedicines
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAutism Spectrum Disorder
dc.subjectUltra-rare variants
dc.subjectProtein–protein interaction analysis
dc.subjectSynaptic and neurotransmitter genes
dc.subjectCommunity detection analysis
dc.titleIdentification of neurotransmission and synaptic biological processes Disrupted in Autism Spectrum Disorder using interaction networks and community detection analysis
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue11
oaire.citation.titleBiomedicines
oaire.citation.volume11
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameMaria Rasga
person.givenNameCélia
person.identifier.ciencia-idA212-A40C-4A5D
person.identifier.orcid0000-0002-9969-6241
relation.isAuthorOfPublication6e25ea69-ae28-4926-b81f-54f34151d71b
relation.isAuthorOfPublication.latestForDiscovery6e25ea69-ae28-4926-b81f-54f34151d71b

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