A role for gene-environment interactions in Autism Spectrum Disorder is suggested by variants in genes regulating exposure to environmental factors

Abstract

Introduction: Autism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder defined by deficits in social communication and interaction and repetitive and stereotyped interests and behaviors. ASD heritability estimates of 50-83% support a strong role of genetics in its onset, with large sequencing studies reporting a high burden of rare potentially pathogenic copy number variants (CNVs) and single nucleotide variants (SNVs) in affected subjects. Recent data strongly suggests that prenatal to postnatal exposure to ubiquitous environmental factors (e.g. environmental toxins, medications and nutritional factors) contribute to ASD risk. Detoxification processes and physiological permeability barriers (i.e. blood-brain barrier, placenta and respiratory cilia) are crucial in regulating exposure and response to external agents during early development. Thus, the objectives of this study were: 1) to find genes involved in detoxification and regulation of barriers permeability with a high load of relevant CNVs and SNVs in ASD subjects; 2) to explore interactions between the identified genes and environmental factors relevant for the disorder. Material and Methods: Through literature and databases review we searched for genes involved in detoxification and regulation of barriers permeability processes. Genetic data collected from large datasets of subjects with ASD (Autism Genome Project (AGP), Simmons Simplex Collection (SSC), and Autism Sequencing Consortium (ASC)) was used to identify potentially pathogenic variants targeting detoxification and barrier genes. Data from control subjects without neuropsychiatric disorder history was used for comparison purposes. The Comparative Toxicogenomics Database (CTD) was interrogated to identify putatively relevant gene-environment interactions reported in humans throughout the literature. Results:We compiled a list of 519 genes involved in detoxification and regulation of permeability barriers. The analysis of AGP and SSC data resulted in the identification of 7 genes more-frequently targeted by CNVs in ASD subjects from both datasets, after Bonferroni correction for multiple testing (AGP: P<3.5211x10 -4 ; SSC: P< 4.587x10 -4 ). Moreover, 8 genes were exclusively targeted by CNVs from ASD subjects. Regarding SNVs analyses using the ASC dataset, we found 40 genes targeted by potentially pathogenic loss-of-function and/or missense SNVs exclusive to 6 or more cases. The CTD was interrogated for interactions between 55 identified genes and 54 terms for unique chemicals associated with the disorder. A total of 212 gene-environment interaction pairs, between 51/55 (92.7%) genes and 38/54 (70.4%) chemicals, putatively relevant for ASD, were discovered. ABCB1, ABCG2, CYP2C19, GSTM1, CYP2D6, and SLC3A2 were the genes that interacted with more chemicals, while valproic acid, benzo(a)pyrene (b(a)p), bisphenol A, particulate matter and perfluorooctane sulfonic acid (PFOS) were the top chemicals. Discussion: The identified genes code for functionally diverse proteins...

Expression, Regulation, and Functions of the Galectin-16 Gene in Human Cells and Tissues

“…Copy number variations were identified in chromosome 19 for multiple genes including LGALS16 in association with clinical features, such as histological type, ethnicity, disease stage, and familial history, of breast cancer using tumor samples from a Brazilian cohort [ 63 ]. In addition, LGALS16 was determined to be a moderate impact variant associated with autism spectrum disorder, consisting of a missense single nucleotide variant (SNV), which was reported as detrimental by bioinformatic tools SIFT and PolyPhen-2 [ 64 ]. LGALS16 also had greater SNVs within the 3′ flank region with one or more mutations in patients with diffuse large B-cell lymphoma [ 65 ].…”

Analysis of Gene-Environment Interactions Related to Developmental Disorders

“…Public databases such as the Comparative Toxicogenomic Database (CTD) ( Davis et al, 2021 ), Gene Expression Omnibus (GEO) ( Clough and Barrett, 2016 ), Simons Simplex Collection (SSC) ( Fischbach and Lord, 2010 ), and Autism Sequencing Consortium (ASC) ( Buxbaum et al, 2012 ) can be used to discover novel interactions between chemicals and genes associated with DDs. For example, an integrative analysis using CTD, SSC, and ASC revealed a total of 212 gene–environment interaction pairs putatively relevant for ASD, and provided a list of candidate genes susceptible to chemicals associated with ASD, such as valproic acid, benzo(a)pyrene, bisphenol A, particulate matter, and perfluorooctane sulfonic acid ( Santos et al, 2019 ). A novel in silico approach using GEO identified tumor suppressors: p53, retinoblastoma 1, and Kr ü ppel-like factor 8 as leading nodes in the network of developmental neurotoxicity of selective serotonin reuptake inhibitors and antidepressants associated with ASD ( Li et al, 2021 ).…”

The Role of Genetics, Epigenetics, and the Environment in ASD: A Mini Review

“…According to recent studies, more than one thousand autism genes have been investigated. Using the SFARI gene platform, approximately 212 genes (environment interacting genes) have been studied [ 37 , 38 ]. More recently, studies reported that dysregulated gene expression is associated with inflammatory cytokines and behavioural severity in ASD [ 39 , 40 ].…”