High Frequency of CNVs Targeting Genes That Regulate Exposure to Toxicants in Autism Spectrum Disorder (ASD) – a Role for Gene-Environment Interactions

Thursday, May 11, 2017: 12:00 PM-1:40 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
J. X. Santos1,2, C. Rasga1,2, M. Asif1,2, A. R. Marques1,2 and A. M. Vicente1,2,3, (1)Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), Lisbon, Portugal, (2)Biosystems and Integrative Sciences Institute (BioISI), Lisbon, Portugal, (3)Instituto Gulbenkian de Ciência, Oeiras, Portugal

ASD is a neurodevelopmental disorder characterized by complex clinical presentation and multifactorial etiology. While genetic variants, including Copy Number Variants (CNV), are responsible for a substantial fraction of ASD etiology, pre-, peri- and post-natal exposure to environmental factors has also been implicated. Permeability barriers, such as placenta and blood-brain barrier (BBB), are crucial in limiting the exposure to toxicants, particularly during neurodevelopment, while detoxification is fundamental for removal of toxic substances from the organism. Genes encoding molecules involved in these processes are therefore obvious candidates to mediate an increased genetic susceptibility to environmental toxicants in ASD.


In this study we seek to identify genetic variants that may interact with environmental factors in ASD.


Genes relevant for detoxification and permeability of the BBB or the placenta to environmental toxicants were selected through literature review and databases (Human Protein Atlas and The Toxin and Toxin-Target Database). We examined the frequency of CNVs deleting or duplicating selected detoxification and permeability genes in ASD subjects genotyped by the Autism Genome Project (N=2157), and compared with CNV frequencies in a control dataset (N=10355), available from the Database of Genomic Variants (DGV). ASD and control subjects were genotyped using Illumina platforms. Statistical analysis was performed using SPSS, and Bonferroni correction for multiple testing was applied. Pathway enrichment analysis was performed using STRING.


We identified 491 genes involved in detoxification or permeability for toxic substances. In 1107 ASD individuals (51%) we found that 240 (49%) of the selected genes were targeted by CNVs. Comparing with a control subject dataset, we identified 51 genes (21%) exclusively found in CNVs from 88 ASD patients (4%). CYP2D6 was the most frequently targeted gene (in 16 ASD subjects, 0.74%), followed by GAL3ST2, ARSF and TRIM64B, targeted by CNVs found in 6, 5 and 4 ASD patients, respectively. From the 189 genes identified in CNVs from both patient and control subjects, 40 genes were significantly more frequent in CNVs from individuals with ASD compared with controls, after correction for multiple testing (P<2.6x10-4). Many of the ASD-exclusive or associated genes clustered in xenobiotics-related processes (eg. CYP450 and UGT genes), in transport mechanisms (ABCB1, SLC2A3 and SLC2A14) or in tight-junctions function (CLDN5, OCLN, PARD6G and PRKCZ); others, like COMT and SHANK2, were previously implicated in ASD etiology.


This work reinforces the hypothesis that interactions between environmental exposure and genetic variation may contribute to ASD. Some of the genes more frequently deleted/duplicated in ASD subjects are part of ubiquitous metabolic or transport pathways, suggesting overarching sensitivities to a wide variety of toxicants. Others, with specific targets, may identify the most damaging toxicants for genetically susceptible individuals, suggesting preventive and therapeutic measures. Clinical correlations are currently being explored.

See more of: Genetics
See more of: Genetics