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Exploring mechanisms of gene-environment interactions contributing to the onset of idiopathic Autism Spectrum Disorder

2020-06Conference object Restricted access
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dc.contributor.authorXavier Santos, João
dc.contributor.authorMartiniano, Hugo
dc.contributor.authorMarques, Ana Rita
dc.contributor.authorRasga, Célia
dc.contributor.authorVilela, Joana
dc.contributor.authorMoura Vicente, Astrid
dc.date.accessioned2021-03-17T11:39:16Z
dc.date.available2021-03-17T11:39:16Z
dc.date.issued2020-06
dc.description.abstractSequencing studies have yielded several candidate genes for Autism Spectrum Disorder (ASD). However, the biological mechanisms underlying its onset are still unclear. Environmental factors may modulate ASD risk, with heritability estimates of 50-80% supporting a role for gene-environment interactions in idiopathic cases. We hypothesize that ASD candidate genes interact with reported ubiquitous environmental risk factors. Thus, we interrogated the Comparative Toxicogenomics Database (CTD) for interactions between 1144 ASD candidate genes and 59 ASD-risk chemicals. A proportion analysis was performed to identify genes that selectively interact with ASD risk chemicals (and vice-versa). Genetic data from ASD-individuals was inspected to identify SNVs (n=2674) and CNVs (n=3570). Eleven genes, including genes encoding for sex hormone receptors (AR, ESR1 and ESR2), signaling kinases (MAPK1 and MAPK3) and xenobiotics-responding molecules (GSTM1 and SLC7A5) were found to selectively interact with ASD-chemicals. Meanwhile, heavy metals, endocrine disruptors (pesticides, benzo(a)pyrene and a phthalate) and valproic acid were found to selectively target ASD-candidate genes. In ASD-cases, we found 22 loss-of-function or deleterious missense SNVs in 8/11 genes, of which 3 (ESR1, ESR2, and MAPK3) were also targeted by CNVs. External cues may dysregulate the MAPK signaling cascade, leading to neurodevelopmental problems. Hormone-mimicking toxins act as agonist/antagonist ligands to hormone receptors, while SLC7A5 is a blood-brain barrier (BBB) transporter. Sex hormones and BBB are fundamental during early development. We highlight the need of considering genetics and environment as interacting entities. Efforts to collect early-life exposure data from genetically susceptible patients may accelerate the implementation of health management strategies for ASD.pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7516
dc.language.isoengpt_PT
dc.publisherInstituto Nacional de Saúde Doutor Ricardo Jorge, IPpt_PT
dc.subjectAutism Spectrum Disorderpt_PT
dc.subjectASDpt_PT
dc.subjectAutismpt_PT
dc.subjectEnvironmental Factorspt_PT
dc.subjectPerturbações do Desenvolvimento Infantil e Saúde Mentalpt_PT
dc.subjectAutismopt_PT
dc.titleExploring mechanisms of gene-environment interactions contributing to the onset of idiopathic Autism Spectrum Disorderpt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlace(online)pt_PT
oaire.citation.title53rd European Society of Human Genetics (ESHG) Conference, 6-9 june 2020pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typeconferenceObjectpt_PT

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