Gene- Environment Intereactions in Austim Spectrum Disorders ASD

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Gene-environment interactions in Autism Spectrum Disorder (ASD)

Publication . Santos, João Xavier; Vicente, Astrid Moura; Nunes, Ana

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and interaction and repetitive and restricted behaviors. While heritability estimates support a role for gene-environment interactions in ASD etiology, there is a paucity of strategies that integrate both components. The objective of this work was to identify gene-environment interactions involved in ASD risk. Through a systematic literature review we identified neurotoxic xenobiotics previously implicated in ASD, including air pollutants and endocrine disruptors. Using a school-based screening strategy we provide an updated prevalence estimate for 7-9 years old children from Centro Region of Portugal, of 0.5% (95% CI: 0.3-0.7). Leveraging public air quality monitoring data we estimated early-life exposure to criteria air pollutants in 217 ASD-subjects, and show that exposure to particulate matter during critical neurodevelopmental windows is associated with a higher clinical severity of ASD. In silico inspection of large genetic datasets (N=6224) showed that ASD-subjects carry predicted-damaging variants in a panel of 77 genes involved in the regulation of detoxification and physiological barriers (blood-brain barrier and placenta) permeability (XenoReg genes). Database query indicates that these genes interact with ASD-implicated xenobiotics. Through biochemical analyses of neonatal dried blood spots and the piloting of an early-life exposures assessment questionnaire we retrospectively collected environmental data for 70 ASD-children. The integration of environmental and sequencing data revealed a group of 13 patients for whom gene-environment interactions likely contributed to disease etiology. We present evidence that genetically-susceptible subjects might be at higher risk of ASD due to an increased vulnerability to early-life exposures. Possible underlying neuropathological mechanisms, including neuroinflammation, oxidative stress, endocrine disruption and epigenetics, warrant experimental validation. This work reinforces the need for clinical stratification and for monitoring early-life exposures, providing knowledge that, prospectively, may be translated to personalized medicine strategies applied in clinical practice.

2023-01Tese de doutoramento

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

PD/BD/114386/2016