Autism Spectrum Disorder Susceptibility Research Articles

Dysfunction of striatal parvalbumin interneurons drives motor stereotypies in Cntnap2-/- mouse model of autism spectrum disorders.

The involvement of parvalbumin (PV) interneurons in autism spectrum disorders (ASD) pathophysiology has been widely described without clearly elucidating how their dysfunctions could lead to ASD symptoms. The Cntnap2-/- mice, an ASD mouse model deficient for a major ASD susceptibility gene, display core ASD symptoms including motor stereotypies, which are directly linked to striatal dysfunction. This study reveals that striatal PV interneurons display hyperexcitability and hyperactivity in Cntnap2-/- mice, along with a reduced response in medium spiny neurons. We also provide evidence for a crucial role of striatal PV interneurons in motor stereotypies by demonstrating that their selective inhibition rescued a wild type-like phenotype. Our study identifies how PV interneuron dysfunctions disrupt striatal circuitry and drive the motor stereotypies in ASD.

Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability.

Rare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability. In a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability. Bottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD. Our findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.

Large-Scale Whole Genome Sequence Analysis of >22,000 Subjects Provides no Evidence of FMR1 Premutation Allele Involvement in Autism Spectrum Disorder.

Expansion of a CGG repeat in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome is the cause of Fragile X Syndrome (FXS). The repeat length of unaffected individuals varies between 5-40 repeats, whereas >200 repeats are observed in cases of FXS. The intermediate range between 55-200 repeats is considered the premutation range and is observed in roughly 1:300 females and 1:900 males in the general population. With the availability of large-scale whole genome sequence (WGS) data and the development of computational tools to detect repeat expansions, we systematically examined the role of FMR1 premutation alleles in autism spectrum disorder (ASD) susceptibility, assess the prevalence, and consider the allelic stability between parents and offspring. We analyzed the WGS data of 22,053 subjects, including 32 FXS positive controls, 1359 population controls, and 5467 ASD families. We observed no FMR1 full mutation range repeats among the ASD parent-offspring families but identified 180 family members with premutation range alleles, which represents a higher prevalence compared to the independent WGS control sample and previous reports in the literature. A sex-specific analysis between probands and unaffected siblings did not reveal a significant increase in the burden of premutation alleles in either males or females with ASD. PCR validation, however, suggests an overestimation of the frequency of FMR1 premutation range alleles through computational analysis of WGS data. Overall, we show the utility of large-scale repeat expansion screening in WGS data and conclude that there is no apparent evidence of FMR1 premutation alleles contributing to ASD susceptibility.

Diagnostic yield and clinical impact of chromosomal microarray analysis in autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by high heritability estimates and recurrence rates; its genetic underpinnings are very heterogeneous and include variable combinations of common and rare variants. Array-comparative genomic hybridization (aCGH) offers significant sensitivity for the identification of copy number variants (CNVs), which can act as susceptibility or causal factors for ASD. The aim of this study was to evaluate both diagnostic yield and clinical impact of aCGH in 329 ASD patients of Italian descent. Pathogenic/likely pathogenic CNVs were identified in 50/329 (15.2%) patients, whereas 89/329 (27.1%) carry variants of uncertain significance. The 10 most enriched gene sets identified by Gene Ontology Enrichment Analysis are primarily involved in neuronal function and synaptic connectivity. In 13/50 (26.0%) patients with pathogenic/likely pathogenic CNVs, the outcome of array-CGH led to the request of 25 additional medical exams which would not have otherwise been prescribed, mainly including brain MRI, EEG, EKG, and/or cardiac ultrasound. A positive outcome was obtained in 12/25 (48.0%) of these additional tests. This study confirms the satisfactory diagnostic yield of aCGH, underscoring its potential for better, more in-depth care of children with autism when genetic results are analyzed also with a focus on patient management.

Investigation of autism-related transcription factors underlying sex differences in the effects of bisphenol A on transcriptome profiles and synaptogenesis in the offspring hippocampus

BackgroundBisphenol A (BPA) has been linked to susceptibility to autism spectrum disorder (ASD). Our recent studies have shown that prenatal BPA exposure disrupted ASD-related gene expression in the hippocampus, neurological functions, and behaviors associated with ASD in a sex-specific pattern. However, the molecular mechanisms underlying the effects of BPA are still unclear.MethodsTranscriptome data mining and molecular docking analyses were performed to identify ASD-related transcription factors (TFs) and their target genes underlying the sex-specific effects of prenatal BPA exposure. Gene ontology analysis was conducted to predict biological functions associated with these genes. The expression levels of ASD-related TFs and targets in the hippocampus of rat pups prenatally exposed to BPA were measured using qRT-PCR analysis. The role of the androgen receptor (AR) in BPA-mediated regulation of ASD candidate genes was investigated using a human neuronal cell line stably transfected with AR-expression or control plasmid. Synaptogenesis, which is a function associated with genes transcriptionally regulated by ASD-related TFs, was assessed using primary hippocampal neurons isolated from male and female rat pups prenatally exposed to BPA.ResultsWe found that there was a sex difference in ASD-related TFs underlying the effects of prenatal BPA exposure on the transcriptome profiles of the offspring hippocampus. In addition to the known BPA targets AR and ESR1, BPA could directly interact with novel targets (i.e., KDM5B, SMAD4, and TCF7L2). The targets of these TFs were also associated with ASD. Prenatal BPA exposure disrupted the expression of ASD-related TFs and targets in the offspring hippocampus in a sex-dependent manner. Moreover, AR was involved in the BPA-mediated dysregulation of AUTS2, KMT2C, and SMARCC2. Prenatal BPA exposure altered synaptogenesis by increasing synaptic protein levels in males but not in females, but the number of excitatory synapses was increased in female primary neurons only.ConclusionsOur findings suggest that AR and other ASD-related TFs are involved in sex differences in the effects of prenatal BPA exposure on transcriptome profiles and synaptogenesis in the offspring hippocampus. These TFs may play an essential role in an increased ASD susceptibility associated with endocrine-disrupting chemicals, particularly BPA, and the male bias of ASD.

Association between RIT2 rs16976358 Polymorphism and Autism Spectrum Disorder in Asian Populations: A Meta-analysis.

Recent studies have shown that Ras-like without CAAX2 (RIT2) polymorphism is a susceptible factor for Parkinson's disease (PD) and autism spectrum disorder (ASD). SNP rs12456492 and rs16976358 show the emerging evidence of increased risk of PD and ASD, respectively. A meta-analysis examining the relationship between rs12456492 and PD was reported, but the association between rs16976358 and ASD has not been investigated. We searched literature from the databases PubMed, Embase, Google Scholar, ScienceDirect, EBSCOhost, OVID, Web of Science, and Wiley up to February 2021. Three studies including 1160 ASD cases and 1367 controls were eventually enrolled in the meta-analysis based on strict inclusion and exclusion criteria. All genetics models indicate a significant association between rs16976358 polymorphism and ASD susceptibility (C vs. T: p = 0.001; CC vs. TT: p = 0.001; CT vs. TT: p = 0.009; CC+CT vs. TT: p = 0.001; CC vs. CT+TT: p = 0.001; TT+CC vs. CT: p = 0.013). The results of sensitivity analysis and publication bias of Begg's and Egger's tests were stable in the models of allele (C vs. T), codominant (CC vs. TT), dominant (CC+CT vs. TT), and recessive (CC vs. CT+TT). Our meta-analysis exhibits that the allele C, CC, and CT genotyping of rs16976358 suggest the risk for ASD, but additional studies using a large sample size and ethnically diverse populations need to be included in the future.

Preterm birth and weight-for-gestational age for risks of autism spectrum disorder and intellectual disability: A nationwide population-based cohort study

To evaluate gestational age (GA) and small-for-gestational age (SGA) as continuums and gender on the incidences of autism spectrum disorder (ASD) and co-occurring intellectual disability (ID). This is a population-based cohort study using the 2004-2008 Taiwan Maternal and Child Health Database. The diagnosis of ASD was determined by International Classification of Diseases, 9th Revision (ICD-9). Generalized estimating equations models were fit to evaluate associations between perinatal variables and ASD. This study included 916,315 individuals. A total of 9474 (1.0%) children were diagnosed with ASD, among whom 1594 (16.8%) had co-occurring ID. Lower GA carried higher odds of ASD with ID (GA < 28 weeks, aOR: 4.26, 95% CI: 2.13, 8.50; GA 28-30 weeks, aOR: 2.80, 95% CI: 1.57, 4.97; GA 31-33 weeks, aOR: 1.63, 95% CI: 1.05, 2.55; GA 34-36 weeks, aOR: 1.39, 95% CI: 1.16, 1.67) and ASD without ID (GA < 28 weeks, aOR:2.05, 95% CI: 1.25, 3.36; GA 28-30 weeks, aOR: 2.02, 95% CI: 1.46, 2.79; GA 31-33 weeks, aOR: 1.42, 95% CI: 1.13, 1.77; GA 34-36 weeks, aOR: 1.18, 95% CI: 1.08, 1.29). Male preterm infants had ASD risks negatively correlated to GA, while ASD risks were significantly increased only among female infants born late preterm. The degree of SGA showed a stepwise increased risk for ASD with and without ID in both male and female infants. Lower GA and the degree of SGA are both associated with ASD susceptibility, either with or without co-occurring ID, and remarkably increased the risk of ID.

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

BackgroundPatients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3WT/ΔC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption.MethodsWe recorded sleep behavior in developing Shank3ΔC/ΔC, Shank3WT/ΔC, and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3WT/ΔC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults.ResultsMale and female Shank3ΔC/ΔC mice slept significantly less than wild-type and Shank3WT/ΔC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3WT/ΔC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3WT/ΔC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3WT/ΔC subjects had a significant reduction in risk aversion. CON Shank3WT/ΔC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests.LimitationsThis study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities.ConclusionOur study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

DIP2C polymorphisms are implicated in susceptibility and clinical phenotypes of autism spectrum disorder

BackgroundDisco-interacting protein 2 C (DIP2C) has recently been reported as a new susceptibility gene for autism spectrum disorder (ASD) in a genome-wide association study. MethodsWe evaluated associations between single nucleotide polymorphisms (SNPs) of DIP2C and ASD susceptibility in a case-control study (715 ASD cases and 728 controls) from Chinese Han. ResultsWe identified a significant association between SNPs (rs3740304, rs2288681, rs7088729, rs4242757, rs10795060, and rs10904083) and ASD susceptibility. Of note, rs3740304, rs2288681, and rs7088729 are positively associated with ASD under inheritance models; moreover, haplotypes with any two marker SNPs (rs3740304 [G], rs2288681 [C], rs7088729 [T], rs4242757 [C], rs10795060 [G], and rs10904083 [A]) are also significantly associated with ASD. Additionally, rs10795060 and rs10904083 are associated with “visual reaction” phenotypes of ASD. ConclusionsDIP2C polymorphisms sort out the susceptibility and clinical phenotypes of autism spectrum disorder.

CRISPR-mediated activation of autism gene Itgb3 restores cortical network excitability via mGluR5 signaling

Many mutations in autism spectrum disorder (ASD) affect a single allele, indicating a key role for gene dosage in ASD susceptibility. Recently, haplo-insufficiency of ITGB3, the gene encoding the extracellular matrix receptor β3 integrin, was associated with ASD. Accordingly, Itgb3 knockout (KO) mice exhibit autism-like phenotypes. The pathophysiological mechanisms of Itgb3 remain, however, unknown, and the potential of targeting this gene for developing ASD therapies uninvestigated. By combining molecular, biochemical, imaging, and pharmacological analyses, we establish that Itgb3 haplo-insufficiency impairs cortical network excitability by promoting extra-synaptic over synaptic signaling of the metabotropic glutamate receptor mGluR5, which is similarly dysregulated in fragile X syndrome, the most frequent monogenic form of ASD. To assess the therapeutic potential of regulating Itgb3 gene dosage, we implemented CRISPR activation and compared its efficacy with that of a pharmacological rescue strategy for fragile X syndrome. Correction of neuronal Itgb3 haplo-insufficiency by CRISPR activation rebalanced network excitability as effectively as blockade of mGluR5 with the selective antagonist MPEP. Our findings reveal an unexpected functional interaction between two ASD genes, thereby validating the pathogenicity of ITGB3 haplo-insufficiency. Further, they pave the way for exploiting CRISPR activation as gene therapy for normalizing gene dosage and network excitability in ASD.

Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes

Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10−4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

SHANK3 genetic polymorphism and susceptibility to ASD: evidence from molecular, in silico, and meta-analysis approaches.

The SHANK3 gene encodes a master synaptic scaffolding protein at the excitatory synapse's postsynaptic density, which is predominantly responsible for constructing a synapse, maintaining synaptic structure, and functions. Recently, evidence from rare mutations and copy number variation provided an important clue about SHANK3 which acts as a strong candidate gene in the pathogenesis of Autism Spectrum Disorder (ASD). To investigate potential allelic variants for the SHANK3 (rs9616915) gene as a genetic risk factor, we performed PCR-RFLP analysis and Sanger sequencing for 90 ASD and 90 healthy subjects. Moreover, to understand the functional and structural impacts of our selected non-synonymous SHANK3 SNP rs9616915, we have performed an in silico analysis. Subsequently, a meta-analysis of rs9616915 with a total of 6 eligible studies (including the present study) containing a total of 795 cases and 12,947 controls was obtained from a comprehensive online database search to evaluate the overall association with ASD. Our retrieved data, such as Pearson's chi-square test (p = 0.081) as well as logistic regression analysis of co-dominant (p = 0.1131), dominant (p = 0.3656) and recessive models (p = 0.0569) speculated no significant association between rs9616915 and our studied sample. Interestingly, by in silico analysis, we have observed two hydrogen bonds between amino acids instead of one hydrogen bond in the protein structure of rs9616915, which indicates this mutant structure could affect the proteins' stability. The findings of the meta-analysis revealed that four genetic association models were associated with ASD susceptibility. Our study suggested that targeted SHANK3 SNP of interest rs9616915 might not be associated with ASD in the southern part of the Bangladeshi population.

A Combined Proteomics and Metabolomics Profiling to Investigate the Genetic Heterogeneity of Autistic Children.

Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces significant challenges due to the existence of heterogeneity. In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out. The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, peripheral blood mononuclear cells, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focuses on several common and previously reported mechanisms of ASD. The biomarkers for ASD diagnosis could be found by taking differentially expressed proteins and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.

Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility.

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background.

Sequencing of selected chromatin remodelling genes reveals increased burden of rare missense variants in ASD patients from the Japanese population

Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case–control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein–protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility.

Maternal Immune Activation and Interleukin 17A in the Pathogenesis of Autistic Spectrum Disorder and Why It Matters in the COVID-19 Era.

Autism spectrum disorder (ASD) is the commonest neurodevelopmental disability. It is a highly complex disorder with an increasing prevalence and an unclear etiology. Consensus indicates that ASD arises as a genetically modulated, and environmentally influenced condition. Although pathogenic rare genetic variants are detected in around 20% of cases of ASD, no single factor is responsible for the vast majority of ASD cases or that explains their characteristic clinical heterogeneity. However, a growing body of evidence suggests that ASD susceptibility involves an interplay between genetic factors and environmental exposures. One such environmental exposure which has received significant attention in this regard is maternal immune activation (MIA) resulting from bacterial or viral infection during pregnancy. Reproducible rodent models of ASD are well-established whereby induction of MIA in pregnant dams, leads to offspring displaying neuroanatomical, functional, and behavioral changes analogous to those seen in ASD. Blockade of specific inflammatory cytokines such as interleukin-17A during gestation remediates many of these observed behavioral effects, suggesting a causative or contributory role. Here, we review the growing body of animal and human-based evidence indicating that interleukin-17A may mediate the observed effects of MIA on neurodevelopmental outcomes in the offspring. This is particularly important given the current corona virus disease-2019 (COVID-19) pandemic as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is a potent stimulator of the maternal immune response, however the long-term effects of maternal SARS-CoV-2 infection on neurodevelopmental outcomes is unclear. This underscores the importance of monitoring neurodevelopmental outcomes in children exposed to SARS-CoV-2-induced MIA during gestation.

MCP-1 Signaling Disrupts Social Behavior by Modulating Brain Volumetric Changes and Microglia Morphology.

Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.

Potassium channels and autism spectrum disorder: An overview.

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted, repetitive patterns of behaviors, interests, or activities. It had been demonstrated that potassium channels played a key role in regulating neuronal excitability, which was closely associated with neurological diseases including epilepsy, ataxia, myoclonus, and psychiatric disorders. In recent years, a growing body of evidence from whole-genome sequencing and whole-exome sequencing had identified several ASD susceptibility genes of potassium channels in ASD subjects. Genetically dysfunction of potassium channels may be involved in altered neuronal excitability and abnormal brain function in the pathogenesis of ASD. This review summarizes current findings on the features of ASD-risk genes (KCND2, KCNQ2, KCNQ3, KCNH5, KCNJ2, KCNJ10, and KCNMA1) and further expatiate their potential role in the pathogenicity of ASD.

UTMOST, a single and cross-tissue TWAS (Transcriptome Wide Association Study), reveals new ASD (Autism Spectrum Disorder) associated genes

Autism spectrum disorders (ASD) is a complex neurodevelopmental disorder that may significantly impact on the affected individual’s life. Common variation (SNPs) could explain about 50% of ASD heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools, such as TWAS (Transcriptome Wide Association Studies) which integrate tissue expression and genetic data, are a great approach to identify new ASD susceptibility genes. The main goal of this study is to use UTMOST with the publicly available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, an in silico biological characterization for the novel associated loci was performed. Our results have shown the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2, and PTPRE) and have highlighted the association of NKX2-2, MANBA, ERI1, and MITF at the gastrointestinal level. The gastrointestinal associations are quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association of NKX2-2 and BLK. UTMOST-associated genes together with their in silico biological characterization seems to point to different biological mechanisms underlying ASD etiology. Thus, it would not be restricted to brain tissue and it will involve the participation of other body tissues such as the gastrointestinal.

Genetic Variations Influencing Glucose Homeostasis and Insulin Secretion and their Associations with Autism Spectrum Disorder in Kazakhstan

Introduction: There is a complex interaction between glucose and insulin homeostasis pathways, diabetes and autism spectrum disorder (ASD). It is known that neuronal migration pathways may be interrupted by intrauterine hyperinsulinemia and hyperglycemia. Moreover, neonatal hypoglycemia which is related to mitochondrial dysfunction has a potential role that influences ASD pathogenesis [6,7]. We present here a preliminary case-control study on children and adolescents (8 – 15 years old) with and without autism spectrum disorder examining the association between genetic polymorphisms impacting glucose and insulin homeostasis and autism spectrum disorder in Kazakhstan. Methods: In this case-control study looking at 211 samples, associations of glucose and insulin homeostasis gene polymorphisms of 10 genes and demographic variables with autism spectrum disorder were examined. Fisher’s exact test and multivariate logistic regression models were used to find associations between polymorphisms and other predictors. Results: Preliminary results suggest that there is a complex relation between autism spectrum disorder and genetic variations that are associated with impaired glucose and insulin homeostasis susceptibility. There is a significant association of the T allele of ADIPOQ (rs1501299) (OR=1.75, 95% CI:1.04-2.93, p-value=0.035); the T allele of GCKR (rs1260326) (OR=0.6, 95% CI:0.39-0.93, p-value=0.023); the T allele of SLC30A8 (rs13266634) (OR=1.77, 95% CI:1.12-2.78, p-value=0.014); and the recessive GG genotype of rs10757278 (CDKN2B) (OR=2.58, 95% CI: 1.24-5.36, p-value=0.011) with autism spectrum disorder in the Kazakhstan population. Conclusion: Overall, this preliminary study revealed that there is evidence of significant associations between glucose and insulin homeostasis gene polymorphisms and autism spectrum disorder susceptibility in Kazakhstan and further study in this area to further verify this, is needed.