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

AbstractIntroductionAutism 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 MethodsThrough 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.ResultsWe 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<3.5211×10−4; SSC: P< 4.587×10−4). 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.DiscussionThe identified genes code for functionally diverse proteins, ranging from enzymes that increase the degradability of xenobiotics (CYP450s, UGTs and GSTs), to transporters (ABCs and SLCs), proteins that regulate the correct function of barriers (claudins and dyneins) and placental hormones. The identified gene-environment interactions may reflect the fact that some genes and chemicals are understudied and that the potential neurotoxicity of many substances is unreported. We suggest that environmental factors can have pathogenic effects when individuals carry variants targeting these genes and discuss the potential mechanisms by which these genes can influence ASD risk.ConclusionWe reinforce the hypothesis that gene-environment interactions are relevant, at least, for a subset of ASD cases. Given that no treatment exists for the pathology, the identification of relevant modifiable exposures can contribute to the development of preventive strategies for health management policies in ASD.

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The Effect of Prenatal Valproate Exposure in Serotonin Transporter Knockout Rats On Anxiety and Cognition: A Gene*Environment Interaction Model of Autism Spectrum Disorder

10.26686/wgtn.17013839.v1 ◽

2021 ◽

Author(s):

◽

Caren L. August

Keyword(s):

Autism Spectrum Disorder ◽

Cognitive Ability ◽

Serotonin Transporter ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Environment Interaction ◽

Gene Environment Interaction ◽

Gene Environment ◽

Starting Point

<p>Autism Spectrum Disorder is a complex neurodevelopmental disorder which is often associated with increased anxiety and deficits in cognitive ability. The present research investigated a potential gene*environment interaction between two factors previously implicated in ASD in a rat model; prenatal exposure to valproate (VPA) and genetic reduction of the serotonin transporter (SERT). Wildtype and heterozygous SERT knockout rats prenatally exposed to VPA or saline on gestational day12.5 (G12.5) were assessed on measures of anxiety: elevated plus-maze and novelty suppressed-feeding and cognitive ability: prepulse inhibition and latent inhibition. A significant main effect was found for VPA exposure in all paradigms, showing increased anxiety-typical behaviour and abnormal cognitive ability. However, no significant effect of genotype or interaction was observed. Results from the present study do not confirm gene*environment interaction between prenatal VPA and heterozygous SERT knockout but this may be due to several factors that are discussed within the thesis. In any case, this study represents a starting point for further studies investigating other combinations of genetic and environmental factors as models of ASD pathogenesis.</p>

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The Effect of Prenatal Valproate Exposure in Serotonin Transporter Knockout Rats On Anxiety and Cognition: A Gene*Environment Interaction Model of Autism Spectrum Disorder

10.26686/wgtn.17013839 ◽

2021 ◽

Author(s):

◽

Caren L. August

Keyword(s):

Autism Spectrum Disorder ◽

Cognitive Ability ◽

Serotonin Transporter ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Environment Interaction ◽

Gene Environment Interaction ◽

Gene Environment ◽

Starting Point

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Effects of gene by microbiome interactions on behavioral and neurobiological phenotypes in a mouse model for autism spectrum disorder

10.1101/2020.04.29.065821 ◽

2020 ◽

Author(s):

Aya Osman ◽

Nicholas L. Mervosh ◽

Ana N. Strat ◽

Katherine R. Meckel ◽

Tanner J. Euston ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Environmental Factors ◽

Mouse Model ◽

Translational Research ◽

Gut Microbiome ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Research Strategies ◽

Stage Of Development

AbstractAutism spectrum disorder (ASD) is a serious neurodevelopmental disorder with a very high prevalence rate and a chronic disease course beginning in early childhood. Despite the tremendous burden of ASD, there are currently no disease-modifying treatments. Like many neuropsychiatric illnesses ASD has a complex pathophysiology driven by genetic and environmental factors. There is interest in identifying modifiable environmental factors as potential translational research strategies for development of therapeutics for ASD. A rapidly growing body of research demonstrates that the resident bacteria of the gastrointestinal tract, collectively the gut microbiome, have profound influence on brain and behavior. This gut-brain signaling pathway is highly relevant to ASD as the microbiome begins to form at birth, is heavily influenced by environmental factors throughout early life, and begins to stabilize at the same stage of development that symptoms of ASD begin to develop. To investigate potential gene x microbiome interactions in a model of ASD, we utilized mutant mice carrying a deletion of the ASD-associated Shank3 gene (Shank3KO), which clinically manifests as Phelan-McDermid syndrome, as a model for genetic risk of ASD. Analysis of the gut microbiome of Shank3KO mice demonstrated genotype effects on both microbiome composition and metabolite production. Behaviorally, Shank3KO mice demonstrate decreased social interactions and have altered anxiety and compulsive-like behaviors. Disruption of the microbiome with broad spectrum antibiotics lead to an exacerbation of all behavioral phenotypes in Shank3KO mice. Additionally, we found that Shank3KO mice had markedly increased changes in gene expression in the prefrontal cortex following microbiome depletion. Taken together, our results suggest a gene x microbiome interaction in this mouse model for ASD and raise the possibility that targeting the microbiome may be a valid translational research strategy in developing therapeutics for ASD.

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An Emerging Gene-Environment Interaction Model: Autism Spectrum Disorder Phenotypes Resulting from Exposure to Environmental Contaminants during Gestation

Developmental Neurotoxicology Research ◽

10.1002/9780470917060.ch25 ◽

2010 ◽

pp. 543-562 ◽

Cited By ~ 1

Author(s):

Darryl B. Hood ◽

Daniel Campbell ◽

Pat Levitt

Keyword(s):

Autism Spectrum Disorder ◽

Environmental Contaminants ◽

Interaction Model ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Environment Interaction ◽

Gene Environment Interaction ◽

Gene Environment

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An Overview of Genetic and Environmental Risk of Autism Spectrum Disorder

Global Clinical and Translational Research ◽

10.36316/gcatr.01.0005 ◽

2019 ◽

pp. 37-44 ◽

Cited By ~ 3

Author(s):

Jianjun Ou ◽

Ruiting Liu ◽

Yidong Shen ◽

Kun Xia ◽

Jingping Zhao

Keyword(s):

Autism Spectrum Disorder ◽

Environmental Factors ◽

Rare Variants ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Copy Number Variations ◽

Spectrum Disorder ◽

Nucleotide Polymorphisms ◽

Genetic And Environmental Factors

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder typically diagnosed in children in the first few years of life. Genetic studies have demonstrated a moderate to high heritability of ASD, but only a limited number of single nucleotide polymorphisms (SNPs) have been identified. Meanwhile, numerous single de novo rare variants and copy number variations have been detected in patients with ASD, which are likely caused by environmental factors. Here we provide an overview of genetic and environmental factors that may contribute to the risk of ASD and we recommend that further study should be focused on both genes and environmental factors, as well as their interactions with the expectation that epigenetic studies will lead to understanding the link between the environment and risk of ASD.

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Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

10.1101/2021.12.24.21268340 ◽

2021 ◽

Author(s):

Ricardo Harripaul ◽

Ansa Rabia ◽

Nasim Vasli ◽

Anna Mikhailov ◽

Ashlyn Rodrigues ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

De Novo ◽

Splice Variants ◽

Neurodevelopmental Disorder ◽

Point Mutations ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Loss Of Function ◽

Candidate Sequence

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that affects about 1 in 55 children worldwide and imposes enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies have investigated ASD genetics in consanguineous populations and point towards AR as an under-appreciated source of ASD variants. Here, we used trio whole exome sequencing (WES) to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. In total, we report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss) and 47% non-synonymous. Our analysis indicates an enrichment of previously identified and candidate AR genes. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID), such as AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335, and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified candidate biallelic exonic loss CNVs a number of trios, implicating genes including DNAH7, and DHRS4/DHRS4L2.

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Specialized Diet Therapies: Exploration for Improving Behavior in Autism Spectrum Disorder (ASD)

Current Medicinal Chemistry ◽

10.2174/0929867327666200217101908 ◽

2020 ◽

Vol 27 (40) ◽

pp. 6771-6786

Author(s):

Geir Bjørklund ◽

Nagwa Abdel Meguid ◽

Maryam Dadar ◽

Lyudmila Pivina ◽

Joanna Kałużna-Czaplińska ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Neurodevelopmental Disorder ◽

Caloric Intake ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Nutritional Deficiencies ◽

Childhood And Adolescence ◽

Restricted Interests ◽

Balanced Diet ◽

The Individual

As a major neurodevelopmental disorder, Autism Spectrum Disorder (ASD) encompasses deficits in communication and repetitive and restricted interests or behaviors in childhood and adolescence. Its etiology may come from either a genetic, epigenetic, neurological, hormonal, or an environmental cause, generating pathways that often altogether play a synergistic role in the development of ASD pathogenesis. Furthermore, the metabolic origin of ASD should be important as well. A balanced diet consisting of the essential and special nutrients, alongside the recommended caloric intake, is highly recommended to promote growth and development that withstand the physiologic and behavioral challenges experienced by ASD children. In this review paper, we evaluated many studies that show a relationship between ASD and diet to develop a better understanding of the specific effects of the overall diet and the individual nutrients required for this population. This review will add a comprehensive update of knowledge in the field and shed light on the possible nutritional deficiencies, metabolic impairments (particularly in the gut microbiome), and malnutrition in individuals with ASD, which should be recognized in order to maintain the improved socio-behavioral habit and physical health.

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Possibility that the Onset of Autism Spectrum Disorder is Induced by Failure of the Glutamine-Glutamate Cycle

Current Molecular Pharmacology ◽

10.2174/1874467213666200319125109 ◽

2020 ◽

Vol 14 (2) ◽

pp. 170-174

Author(s):

Koichi Kawada ◽

Nobuyuki Kuramoto ◽

Seisuke Mimori

Keyword(s):

Autism Spectrum Disorder ◽

Endoplasmic Reticulum ◽

Environmental Factors ◽

Endoplasmic Reticulum Stress ◽

Synapse Formation ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Neurodevelopmental Disease ◽

Number Of Patients ◽

The Brain

: Autism spectrum disorder (ASD) is a neurodevelopmental disease, and the number of patients has increased rapidly in recent years. The causes of ASD involve both genetic and environmental factors, but the details of causation have not yet been fully elucidated. Many reports have investigated genetic factors related to synapse formation, and alcohol and tobacco have been reported as environmental factors. This review focuses on endoplasmic reticulum stress and amino acid cycle abnormalities (particularly glutamine and glutamate) induced by many environmental factors. In the ASD model, since endoplasmic reticulum stress is high in the brain from before birth, it is clear that endoplasmic reticulum stress is involved in the development of ASD. On the other hand, one report states that excessive excitation of neurons is caused by the onset of ASD. The glutamine-glutamate cycle is performed between neurons and glial cells and controls the concentration of glutamate and GABA in the brain. These neurotransmitters are also known to control synapse formation and are important in constructing neural circuits. Theanine is a derivative of glutamine and a natural component of green tea. Theanine inhibits glutamine uptake in the glutamine-glutamate cycle via slc38a1 without affecting glutamate; therefore, we believe that theanine may prevent the onset of ASD by changing the balance of glutamine and glutamate in the brain.

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Toxics ◽

10.3390/toxics9050097 ◽

2021 ◽

Vol 9 (5) ◽

pp. 97

Author(s):

Tristan Furnary ◽

Rolando Garcia-Milian ◽

Zeyan Liew ◽

Shannon Whirledge ◽

Vasilis Vasiliou

Keyword(s):

Autism Spectrum Disorder ◽

Prenatal Exposure ◽

Pesticide Exposure ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Biomedical Literature ◽

Spectrum Disorder ◽

Biological Processes ◽

Genetic Associations ◽

Increased Risk

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

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