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Interações gene-ambiente na perturbação do espetro do autismo
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Advisor(s)
Abstract(s)
A Perturbação do Espetro do Autismo (PEA) tem uma heritabilidade estimada
de 50%, indicativa de uma componente genética que pode ser modulada
por fatores ambientais. A evidência de associação com autismo de
alguns compostos potencialmente tóxicos levou-nos a colocar a hipótese
de que genes envolvidos em processos de destoxificação e regulação da
permeabilidade de barreiras fisiológicas (p. ex. placenta, hematoencefálica)
são candidatos para a PEA. Neste trabalho definimos uma lista de 519
genes de destoxificação e das barreiras de permeabilidade, e comparamos
a frequência de Copy Number Variants (CNVs) nestes genes em 2446
crianças com PEA, recrutadas através do Autism Genome Project (AGP),
com 10355 controlos sem patologia neuropsiquiátrica da Database of Genomic
Variants. Como validação, foram avaliados indivíduos com PEA da
Simons Foundation Autism Research Initiative (SFARI) (N=1124). Verificouse
que 555 (22,7%) indivíduos com PEA apresentavam CNVs contendo 173
dos 519 genes de interesse, 31 dos quais foram encontrados exclusivamente
em pacientes com PEA, enquanto 23 genes eram significativamente
mais frequentes em CNVs de indivíduos com PEA do que em controlos.
Múltiplos dos genes identificados estão envolvidos no transporte através
de barreiras fisiológicas ou na destoxificação de toxinas relevantes para a
PEA. Este estudo reforça a hipótese de que, em indivíduos geneticamente
suscetíveis, a exposição a fatores ambientais potencialmente tóxicos pode
contribuir para a PEA.
Autism Spectrum Disorder (ASD) has an estimated heritability of 50%, indicating a genetic component that may be modulated by the environment. Recent studies implicate exposure to specific toxins in ASD etiology. We thus hypothesize that genes involved in detoxification and regulation of physiological barrier permeability processes (e.g. placenta, blood-brain barrier) are plausible candidates for ASD etiology. In this study we defined a candidate list of 519 detoxification and barrier permeability genes that may interact with toxicants relevant for ASD. We compared the frequency of Copy Number Variants (CNVs) targeting these genes in 2446 ASD patients, recruited through the Autism Genome Project, and 10355 controls without neuropsychiatric disease from the Database of Genomic Variants, and validated results in 1124 ASD subjects from the Simons Foundation Autism Research Initiative. We found that 173 of the 519 detoxification and barrier genes were targeted by CNVs from 555 (22.7%) individuals with ASD. Of these genes, 31 were exclusively targeted by CNVs in ASD subjects and 23 were significantly more frequent in ASD than in controls. Network analysis showed that many of these genes are involved in the transport through physiological barriers or the detoxification of potential toxicants relevant for ASD. This study reinforces the hypothesis that the exposure to environmental factors in genetically susceptible individuals may contribute to ASD risk.
Autism Spectrum Disorder (ASD) has an estimated heritability of 50%, indicating a genetic component that may be modulated by the environment. Recent studies implicate exposure to specific toxins in ASD etiology. We thus hypothesize that genes involved in detoxification and regulation of physiological barrier permeability processes (e.g. placenta, blood-brain barrier) are plausible candidates for ASD etiology. In this study we defined a candidate list of 519 detoxification and barrier permeability genes that may interact with toxicants relevant for ASD. We compared the frequency of Copy Number Variants (CNVs) targeting these genes in 2446 ASD patients, recruited through the Autism Genome Project, and 10355 controls without neuropsychiatric disease from the Database of Genomic Variants, and validated results in 1124 ASD subjects from the Simons Foundation Autism Research Initiative. We found that 173 of the 519 detoxification and barrier genes were targeted by CNVs from 555 (22.7%) individuals with ASD. Of these genes, 31 were exclusively targeted by CNVs in ASD subjects and 23 were significantly more frequent in ASD than in controls. Network analysis showed that many of these genes are involved in the transport through physiological barriers or the detoxification of potential toxicants relevant for ASD. This study reinforces the hypothesis that the exposure to environmental factors in genetically susceptible individuals may contribute to ASD risk.
Description
Keywords
Autismo Perturbação do Espectro do Autismo Perturbações do Desenvolvimento Infantil Perturbações do Desenvolvimento Infantil e Saúde Mental Crianças Saúde Pública Portugal
Pedagogical Context
Citation
Boletim Epidemiológico Observações. 2017;6(Supl 9):29-33
Publisher
Instituto Nacional de Saúde Doutor Ricardo Jorge, IP