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

Xavier Santos, João; Martiniano, Hugo; Marques, Ana Rita; Rasga, Célia; Vilela, Joana; Moura Vicente, Astrid

http://hdl.handle.net/10400.18/7516

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Authors

Moura Vicente, Astrid

Abstract(s)

Sequencing 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.