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Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis

2023-11-04Journal article Open access
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dc.contributor.authorVilela, Joana
dc.contributor.authorMartiniano, Hugo
dc.contributor.authorMarques, Ana Rita
dc.contributor.authorSantos, João Xavier
dc.contributor.authorAsif, Muhammad
dc.contributor.authorRasga, Célia
dc.contributor.authorOliveira, Guiomar
dc.contributor.authorVicente, Astrid Moura
dc.date.accessioned2024-01-03T13:34:42Z
dc.date.available2024-01-03T13:34:42Z
dc.date.issued2023-11-04
dc.description(This article belongs to the Special Issue Neurodevelopmental Disabilities)pt_PT
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 etwork’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.pt_PT
dc.description.sponsorshipThis research was funded by Fundação para a Ciência e a Tecnologia (UIDB/04046/2020 and UIDP/04046/2020 Center grants to BioISI), PAC-POCI-01-0145-FEDER-016428 MEDPERSYST, DeePer—Deep graph learning approaches to personalized medicine (EXPL/CCI-BIO/0126/2021) and the National Institute of Health Doutor Ricardo Jorge. J.V., A.R.M. and J.X.S. are recipients of a fellowship from the BioSys PhD program PD65-2012 (J.V. Ref: PD/BD/131390/2017; A.R.M. Ref: PD/BD/113773/2015; and J.X.S. Ref: PD/BD/114386/2016) from Fundação para a Ciência e a Tecnologia (Portugal)pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBiomedicines. 2023 Nov 4;11(11):2971. doi: 10.3390/biomedicines11112971pt_PT
dc.identifier.doi10.3390/biomedicines11112971pt_PT
dc.identifier.issn2227-9059
dc.identifier.urihttp://hdl.handle.net/10400.18/8814
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationBiosystems and Integrative Sciences Institute
dc.relationBiosystems and Integrative Sciences Institute
dc.relationRegulatory RNAs in Autism Spectrum Disorder - modulation of genomic variant effects on clinical phenotype and brain structure and function
dc.relationAutism Spectrum Disorder ASD: genetic, epigenetic and environmental issues
dc.relationGene- Environment Intereactions in Austim Spectrum Disorders ASD
dc.relation.publisherversionhttps://www.mdpi.com/2227-9059/11/11/2971pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAutism Spectrum Disorderpt_PT
dc.subjectUltra-rare Variantspt_PT
dc.subjectProtein–protein Interaction Analysispt_PT
dc.subjectSynaptic and Neurotransmitter Genespt_PT
dc.subjectCommunity Detection Analysispt_PT
dc.subjectPerturbações do Desenvolvimento Infantil e Saúde Mentalpt_PT
dc.subjectAutism
dc.titleIdentification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleRegulatory RNAs in Autism Spectrum Disorder - modulation of genomic variant effects on clinical phenotype and brain structure and function
oaire.awardTitleAutism Spectrum Disorder ASD: genetic, epigenetic and environmental issues
oaire.awardTitleGene- Environment Intereactions in Austim Spectrum Disorders ASD
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04046%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04046%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F131390%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F113773%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F114386%2F2016/PT
oaire.citation.issue11pt_PT
oaire.citation.startPage2971pt_PT
oaire.citation.titleBiomedicinespt_PT
oaire.citation.volume11pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
oaire.fundingStreamOE
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com a política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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