Autism Spectrum Disorder ASD: genetic, epigenetic and environmental issues

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Publication . Vilela, Joana; Martiniano, Hugo; Marques, Ana Rita; Santos, João Xavier; Rasga, Célia; Oliveira, Guiomar; Vicente, Astrid Moura

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.

2022-08-18Journal article

Open access

Autism Spectrum Disorder: contribution of genetic variants involved in the nonsense-mediated mRNA decay

Publication . Marques, Ana Rita; Santos, João Xavier; Vilela, Joana; Rasga, Célia; Martiniano, Hugo; Oliveira, Guiomar; Romão, Luísa; Moura Vicente, Astrid

Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impairedsocial/communication skills and stereotyped/repetitive behaviors. Genetic factors account for 50-80% of the familialrisk of ASD, but genetic determinants are not fully understood and a role for regulatory processes is plausible. Inthis study, we explored the contribution to ASD etiology of genes involved in an important post-transcriptionalregulatory mechanism implicated in neurodevelopment, the Nonsense-Mediated Decay (NMD). Methods: We first compiled a group of 46 genes encoding NMD factors and regulators. In these genes wesearched for Single Nucleotide Variants (SNVs) and Copy Number Variants (CNVs) in two samples of ASD patients(N=1828 and N=3570, respectively). We observed the frequency of these variants in 60146 controls from gnomADv2.1.1 (for SNVs) and in 10355 controls from the Database of Genomic Variant ( for CNVs). In genes with rarevariants (MAF<1% in controls) predicted to be pathogenic in silico , we further investigated whether these variantsaffect protein domains required for NMD. Results: We identified 270 predicted pathogenic SNVs within 38 genes in 524 ASD patients (28.7% of the total ASDcases) and 38 CNVs located in 18 genes in 38 ASD patients (1% of the ASD cases). Five of these genes, RBM8A , UPF2 , FMR1 , SMG6 and EIF4G1, were previously associated with ASD. We found that 136 variants (122 SNVsand 11 CNVs), in 23 genes, were located within known protein domainsrequired for NMD. These variants, identifiedin 258 ASD patients, may affect proper NMD function and consequently contribute to changes in the expression ofNMD targets. Discussion : In this study we identified genetic variants that may affect NMD function in ASD patients. Since mostNMD targets encode proteins expressed in the brain, we hypothesize that NMD impairment can constitute a riskfactor to ASD pathophysiology. Further studies are needed to better understand the impact of these genetic variantson NMD function and their relevance for ASD.A full understanding of these regulatory mechanisms may constitutean opportunity for the development of therapeutic interventions.

2021-11-18Conference object

Restricted access

Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder

Publication . Marques, Ana Rita; Santos, João Xavier; Martiniano, Hugo; Vilela, Joana; Rasga, Célia; Romão, Luísa; Vicente, Astrid Moura

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with unclear etiology. Many genes have been associated with ASD risk, but the underlying mechanisms are still poorly understood. An important post-transcriptional regulatory mechanism that plays an essential role during neurodevelopment, the Nonsense-Mediated mRNA Decay (NMD) pathway, may contribute to ASD risk. In this study, we gathered a list of 46 NMD factors and regulators and investigated the role of genetic variants in these genes in ASD. By conducting a comprehensive search for Single Nucleotide Variants (SNVs) in NMD genes using Whole Exome Sequencing data from 1828 ASD patients, we identified 270 SNVs predicted to be damaging in 28.7% of the population. We also analyzed Copy Number Variants (CNVs) from two cohorts of ASD patients (N = 3570) and discovered 38 CNVs in 1% of cases. Importantly, we discovered 136 genetic variants (125 SNVs and 11 CNVs) in 258 ASD patients that were located within protein domains required for NMD. These gene variants are classified as damaging using in silico prediction tools, and therefore may interfere with proper NMD function in ASD. The discovery of NMD genes as candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology.

2022-03-13Journal article

Open access

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics

Publication . Santos, João Xavier; Rasga, Célia; Marques, Ana Rita; Martiniano, Hugo; Asif, Muhammad; Vilela, Joana; Oliveira, Guiomar; Sousa, Lisete; Nunes, Ana; Vicente, Astrid M.

Heritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.

2022-05-19Journal article

Open access