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A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics

2022-05-19Journal article Open access
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dc.contributor.authorSantos, João Xavier
dc.contributor.authorRasga, Célia
dc.contributor.authorMarques, Ana Rita
dc.contributor.authorMartiniano, Hugo
dc.contributor.authorAsif, Muhammad
dc.contributor.authorVilela, Joana
dc.contributor.authorOliveira, Guiomar
dc.contributor.authorSousa, Lisete
dc.contributor.authorNunes, Ana
dc.contributor.authorVicente, Astrid M.
dc.date.accessioned2023-01-30T14:58:39Z
dc.date.available2023-01-30T14:58:39Z
dc.date.issued2022-05-19
dc.descriptionFree PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161282/pt_PT
dc.description.abstractHeritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.pt_PT
dc.description.sponsorshipThis work was supported by the Fundação para a Ciência e a Tecnologia (FCT), through funding to the project “Gene-environment interactions in Autism Spectrum Disorder” (Grant PTDC/MED-OUT/28937/2017) and to Research Center Grants UIDB/04046/2020 and UIDP/04046/2020 (to BioISI) and UIDB/00006/2020 (to Centro de Estatística e Aplicações da Universidade de Lisboa). This work used the European Grid Infrastructure (EGI) with the support of NCG-INGRID-PT/INCD (Portugal). This work was produced with the support of INCD funded by the FCT and FEDER under the project 01/SAICT/2016 n◦ 022153. JS, ARM, MA, and JV are fellows of the BioSys Ph.D Program and awardees of scholarships funded by FCT, with references: PD/BD/114386/2016, PD/BD/113773/2015, PD/BD/52485/2014, and PD/BD/131390/2017, respectively. AGP data was collected from patients genotyped in the context of Autism Genome Project (AGP), funded by NIMH, HRB, MRC, Autism Speaks, Hilibrand Foundation, Genome Canada, OGI, and CIHR. ASC data was collected from patients genotyped in the context of Autism Sequencing Consortium supported by NIH grants U01MH100233, U01MH100209, U01MH100229, and U01MH100239.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Neurosci. 2022;16:862315. Epub 2022 May 19. doi: 10.3389/fnins.2022.862315pt_PT
dc.identifier.doi10.3389/fnins.2022.862315pt_PT
dc.identifier.issn1662-4548
dc.identifier.urihttp://hdl.handle.net/10400.18/8474
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontiers Mediapt_PT
dc.relationBiosystems and Integrative Sciences Institute
dc.relationBiosystems and Integrative Sciences Institute
dc.relationCentre of Statistics and its Applications
dc.relationGene- Environment Intereactions in Austim Spectrum Disorders ASD
dc.relationAutism Spectrum Disorder ASD: genetic, epigenetic and environmental issues
dc.relationSYSTEMS MEDICINE APPROACH TO IMPROVE DIAGNOSIS AND PROGNOSIS IN AUTISM SPECTRUM DISORDERS ASD, BASED ON EXTENSIVE GENOMIC, BIOCHEMICAL AND CLINICAL DATA
dc.relationRegulatory RNAs in Autism Spectrum Disorder - modulation of genomic variant effects on clinical phenotype and brain structure and function
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fnins.2022.862315/fullpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAutism Spectrum Disorderpt_PT
dc.subjectBlood-brain barrierpt_PT
dc.subjectDetoxificationpt_PT
dc.subjectGene-environment interactionspt_PT
dc.subjectPlacentapt_PT
dc.subjectXenobiotics exposurept_PT
dc.subjectPerturbações do Desenvolvimento Infantil e Saúde Mentalpt_PT
dc.subjectAutismopt_PT
dc.titleA Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobioticspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardTitleCentre of Statistics and its Applications
oaire.awardTitleGene- Environment Intereactions in Austim Spectrum Disorders ASD
oaire.awardTitleAutism Spectrum Disorder ASD: genetic, epigenetic and environmental issues
oaire.awardTitleSYSTEMS MEDICINE APPROACH TO IMPROVE DIAGNOSIS AND PROGNOSIS IN AUTISM SPECTRUM DISORDERS ASD, BASED ON EXTENSIVE GENOMIC, BIOCHEMICAL AND CLINICAL DATA
oaire.awardTitleRegulatory RNAs in Autism Spectrum Disorder - modulation of genomic variant effects on clinical phenotype and brain structure and function
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-OUT%2F28937%2F2017/PT
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oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F114386%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F113773%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F52485%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F131390%2F2017/PT
oaire.citation.startPage862315pt_PT
oaire.citation.titleFrontiers in Neurosciencept_PT
oaire.citation.volume16pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
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oaire.fundingStreamOE
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project.funder.identifierhttp://doi.org/10.13039/501100001871
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rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
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