Genetics Of Autism Spectrum Disorders Research Articles

Database-assisted screening of autism spectrum disorder related gene set

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social and communication difficulties, along with repetitive behaviors. While genetic factors play a significant role in ASD, the precise genetic landscape remains complex and not fully understood, particularly in non-syndromic cases. The study performed an in silico comparison of three genetic databases. ClinVar, SFARI Gene, and AutDB were utilized to identify relevant gene subset and genetic variations associated with non-syndromic ASD. Gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) network analysis were conducted to elucidate the biological significance of the identified genes. The integrity of ASD-related gene subset and the distribution of their variations were statistically assessed. A subset of twenty overlapping genes potentially specific for non-syndromic ASD was identified. GSEA revealed enrichment of biological processes related to neuronal development and differentiation, synaptic function, and social skills, highlighting their importance in ASD pathogenesis. PPI network analysis demonstrated functional relationships among the identified genes. Analysis of genetic variations showed predominance of rare variants and database-specific distribution patterns. The results provide valuable insights into the genetic landscape of ASD and outline the genes and biological processes involved in the condition, while taking into account that the study relied exclusively on in silico analyses, which may be subject to biases inherent to database methodologies. Further research incorporating multi-omics data and experimental validation is warranted to enhance our understanding of non-syndromic ASD genetics and facilitate the development of targeted research, interventions and therapies.

The genetics of autism spectrum disorder in an East African familial cohort

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions affecting communication and social interaction in 2.3% of children. Studies that demonstrated its complex genetic architecture have been mainly performed in populations of European ancestry. We investigate the genetics of ASD in an East African cohort (129 individuals) from a population with higher prevalence (5%). Whole-genome sequencing identified 2.13 million private variants in the cohort and potentially pathogenic variants in known ASD genes (including CACNA1C, CHD7, FMR1, and TCF7L2). Admixture analysis demonstrated that the cohort comprises two ancestral populations, African and Eurasian. Admixture mapping discovered 10 regions that confer ASD risk on the African haplotypes, containing several known ASD genes. The increased ASD prevalence in this population suggests decreased heterogeneity in the underlying genetic etiology, enabling risk allele identification. Our approach emphasizes the power of African genetic variation and admixture analysis to inform the architecture of complex disorders.

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues.

The Promise of Personalized & Precision Genomics in Autism

Despite recent advances in understanding the etiology of autism spectrum disorder (ASD), an approved and efficacious treatment strategy has yet to be identified. The latter demonstrates that the canonical ASD profiled care is becoming much less beneficial and productive, yet it remains ineffective in preventing or effectively treating the above-mentioned disorder. Meanwhile, the link that might exert reliable control over morbidity, mortality and disabling rates as well as significantly optimize the efficacy of ASD treatment for those who had fallen ill and for persons-atrisk is Personalized & Precision Medicine (PPM). Recent advances in ASD genetics pave the way for implementation of PPM in clinical management of autism. Thus, identification of gene modifiers and epigenetic, transcriptional, and translational regulators of implicated genes is important for a more complete understanding of the genetic risk and the precise roles of specific variants. The inherent complexity and heterogeneity of ASD, often further complicated by comorbid sleep disturbances, epilepsy, or attention deficit hyperactivity disorder (ADHD), has been a prominent impediment to achieving a well-defined treatment algorithm. However, the protocols of symptomatic treatment are not considered in this article, since they have been known for a long time and do not reveal the ideology of personalized targeted therapy. In this review, we have accumulated the latest data from the main areas of pathogenetic target discovery using PPM-based tools and omics technologies, in particular genomics, which hold great promise for the development of personalized preventive diagnostic and therapeutic protocols.

Drug repurposing candidates to treat core symptoms in autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by high heritability and clinical heterogeneity. The main core symptoms are social communication deficits. There are no medications approved for the treatment of these symptoms, and medications used to treat non-specific symptoms have serious side effects. To identify potential drugs for repurposing to effectively treat ASD core symptoms, we studied ASD risk genes within networks of protein-protein interactions of gene products. We first defined an ASD network from network-based analyses, and identified approved drugs known to interact with proteins within this network. Thereafter, we evaluated if these drugs can change ASD-associated gene expression perturbations in genes in the ASD network. This was done by analyses of drug-induced versus ASD-associated gene expression, where opposite gene expression perturbations in drug versus ASD indicate that the drug could counteract ASD-associated perturbations. Four drugs showing significant (p < 0.05) opposite gene expression perturbations in drug versus ASD were identified: Loperamide, bromocriptine, drospirenone, and progesterone. These drugs act on ASD-related biological systems, indicating that these drugs could effectively treat ASD core symptoms. Based on our bioinformatics analyses of ASD genetics, we shortlist potential drug repurposing candidates that warrant clinical translation to treat core symptoms in ASD.

Genetics of autism spectrum disorders and future direction.

Autism spectrum disorders (ASDs) have been increasing in prevalence. ASD is a complex human genetic disorder with high heredity and involves interactions between genes and the environment. A significant inheritance pattern in ASD involves a rare genetic mutation; common copy number variants refer to duplication or deletion of stretches of chromosomal loci or protein-disrupting single-nucleotide variants. Haploinsufficiency is one of the more common single-gene causes of ASD, explaining at least 0.5% of cases. Epigenetic mechanisms, such as DNA methylation, act at an interface of genetic and environmental risk and protective factors. Advances in genome-wide sequencing have broadened the view of the human methylome and have revealed the organization of the human genome into large-scale methylation domains with a footprint over neurologically important genes involved in embryonic development. Psychiatric disorders, including ASD, are expected to be diagnosed based on their genetically regulated pathophysiology and to be linked to their treatment.

Shared genetics between autism spectrum disorder and attention-deficit/hyperactivity disorder and their association with extraversion

BackgroundDeciphering the genetic relationships between autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) may uncover underlining shared pathophysiology as well as inform treatment. MethodsThe summary results of genome-wide association studies on ADHD, ASD, and extraversion were utilized for the analyzes. Genetic correlations between ADHD, ASD, and extraversion were tested using linkage disequilibrium score regression. Causal relationships between ADHD, ASD, and extraversion were investigated using Mendelian randomization (MR) analysis. Novel pleiotropic genomic loci shared by ADHD and ASD were identified using a cross-trait meta-analysis. ResultsExtraversion was positively correlated with ADHD (rg = 0.205) and negatively correlated with ASD (rg = −0.193). The MR analysis showed that ADHD confers a causal effect on ASD (OR: 1.35, 95% confidence interval (CI):1.20–1.52) and vice versa (1.46, 1.38–1.55). Extraversion exerts a causal effect on ADHD only (1.19, 1.05–1.33). The cross-trait meta-analysis identified three novel pleiotropic genomic loci for ADHD and ASD, involving two pleiotropic genes, LINC00461 and KIZ. ConclusionsOur study provides new insights into the shared genetics of ADHD and ASD and their connections with extraversion.

Imaging neural circuit pathology of autism spectrum disorders: autism-associated genes, animal models and the application of in vivo two-photon imaging.

Recent advances in human genetics identified genetic variants involved in causing autism spectrum disorders (ASDs). Mouse models that mimic mutations found in patients with ASD exhibit behavioral phenotypes consistent with ASD symptoms. These mouse models suggest critical biological factors of ASD etiology. Another important implication of ASD genetics is the enrichment of ASD risk genes in molecules involved in developing synapses and regulating neural circuit function. Sophisticated in vivo imaging technologies applied to ASD mouse models identify common synaptic impairments in the neocortex, with genetic-mutation-specific defects in local neural circuits. In this article, we review synapse- and circuit-level phenotypes identified by in vivo two-photon imaging in multiple mouse models of ASD and discuss the contributions of altered synapse properties and neural circuit activity to ASD pathogenesis.

Signaling Pathways and Sex Differential Processes in Autism Spectrum Disorder.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders associated with deficits in social communication and restrictive, repetitive patterns of behavior, that affect up to 1 in 54 children. ASDs clearly demonstrate a male bias, occurring ~4 times more frequently in males than females, though the basis for this male predominance is not well-understood. In recent years, ASD risk gene discovery has accelerated, with many whole-exome sequencing studies identifying genes that converge on common pathways, such as neuronal communication and regulation of gene expression. ASD genetics studies have suggested that there may be a “female protective effect,” such that females may have a higher threshold for ASD risk, yet its etiology is not well-understood. Here, we review common biological pathways implicated by ASD genetics studies as well as recent analyses of sex differential processes in ASD using imaging genomics, transcriptomics, and animal models. Additionally, we discuss recent investigations of ASD risk genes that have suggested a potential role for estrogens as modulators of biological pathways in ASD, and highlight relevant molecular and cellular pathways downstream of estrogen signaling as potential avenues for further investigation.

29.1 GENETIC UNDERPINNINGS OF AUTISM SPECTRUM DISORDER

ADHD comorbidity is extremely common in autism spectrum disorder (ASD), and the co-occurrence of traits of ASD with subclinical manifestations of ADHD extends to the general population. In this presentation, data from 4 longitudinal studies collectively involving over 1200 children will be analyzed and the results synthesized to address the issue of overlap in the genetic structure of ADHD and ASD. After considering multiple competing models for the nature of overlap, the preponderance of the available scientific evidence supports a model in which inherited liability indexed by ADHD exerts substantial causal influence on the development of ASD and predicts recurrence among the siblings of affected index cases. The notion that nonspecific insults to neural development, either inherited or acquired, might augment the impact of ASD-specific genetic susceptibilities in contributing to its cause has not been appreciated in the literature on comorbidity, and has significant implications for both personalized intervention and future research. The relationship between early childhood ADHD symptomatology and other heritable predictors of ASD occurrence (and recurrence in families), including ASD traits in first-degree relatives and measures of infant eye tracking and motor coordination, is beginning to be understood as a matrix of independent risk factors that operate jointly in raising risk for ASD. It is conceivable that early treatment of ADHD liability—before the usual onset of the characterizing symptoms of ASD in the second year of life—might ameliorate the severity of ASD syndromes. In order to test this possibility, it will be necessary to develop the technologies to ascertain and quantify ADHD liabilities with higher precision in the first year of life. Given that ADHD appears to be a common contributor to inherited liability for ASD, the statistical power of future biomarker studies, particularly in ASD genetics and neuroimaging, can be enhanced by more comprehensive attention to the measurement of ADHD traits that index causal influences on the disorder, among not only cases but also (importantly) controls.

Autism and Preterm Birth: Clarifying Risk and Exploring Mechanisms.

In the current issue of Pediatrics, the thoughtful work of Crump et al, entitled “Preterm or Early Term Birth and Risk of Autism” has added an important contribution to our understanding of associations between autism and prematurity.1 Building on the strengths of population-based registries, the authors were able to assess 4 061 795 singleton infants born in Sweden between 1973 and 2013 using the Swedish Medical Birth Register (which contains prenatal and birth information) and link clinical diagnoses of autism spectrum disorder (ASD) from hospital, outpatient, and primary care registries. Prevalence rates of ASD were inversely proportional to gestational age: 6.1% for extremely preterm (EPT) (22–27 weeks), 2.6% for very preterm to moderate preterm (28–33 weeks), 1.9% for late preterm (LPT) (34–36 weeks), 1.6% for early term (ET) (37–38 weeks), and 1.4% term (39–41 weeks). After adjusting for covariates and stratifying by sex, prevalence ratios revealed similar trends, ranging from 3.7 to 1.11 among EPT- to ET-born male infants and 4.19 to 1.16 among EPT- to ET-born female infants. In an attempt to assess influences of genetic and/or environmental factors, cosibling analysis was performed, with only modest mitigation of risk.As allowed with large cohort studies, the robust sample size and stratification by gestational age grouping allowed for the important finding that there is increased risk for ASD across the range of prematurity. The findings by Crump et al are consistent with previous work, also from Sweden, suggesting a dose response–type relationship between degree of prematurity and ASD risk.2 The elevated risk even in LPT infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems, social-emotional problems, and psychiatric disorders, some of which may extend to adulthood.3 Indeed, it was the Helsinki Birth Cohort study in which researchers yielded results of late adulthood cognitive impairment among those born LPT.4 In their works, Raju et al have clearly pointed out that infants born even a few weeks before term are at increased risk of respiratory, gastrointestinal, immunologic, and hormonal disturbances5 and that developmental maturation is a continuous process and not always linear. Thus, careful attention should be paid to biological vulnerabilities at later gestational ages. For example, between 34 and 40 weeks, brain weight increases nearly one-third, cortical volume increases nearly 50%, and absolute myelinated white matter volume increases fivefold.6,7Emerging evidence linking behavior and alterations in brain structure, function, and connectivity furthers our understanding of biological and environmental risks. Brain regions predominantly affected by preterm birth are also involved in sensory and social interactions, including white and gray matter.8 In a cohort of very preterm–born infants, Brown et al demonstrated that associations between atypical behavior and degree of white matter injury may be evident as early as term equivalent.9 Using quantitative MRI techniques, Rogers et al reported that disruptions in regional brain circuits at term-equivalent ages in preterm infants predicted social-emotional disturbances at age 5 years.10 As Crump et al point out in their discussion, neuroinflammation, which occurs in response to stress and infection, activate microglia, which results in a cascade of neuronal injury and alterations, pointing to potential mechanisms linking preterm birth to increased risk for ASD. Indeed, there are reports of associations between elevated cytokine levels at birth and subsequent diagnoses of ASD,11,12 and there is contemporary interest in the relationship more generally between immunologic factors and ASD risk.13 It is noted that the vulnerability of the preterm brain structure and function that is exposed to the inflammatory environment of prematurity is present until term gestation.The report by Crump et al is in many ways a definitive accounting of the elevated rates of ASD in preterm infants. And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous. In previous work, researchers suggest that suboptimal obstetric outcomes and perinatal complications may, in some cases, result from underlying ASD etiologies.14 Moreover, even when assuming that prematurity is part of the causal chain leading to ASD outcomes, it will be important to investigate the interactions between the underlying genetics of ASD and the impact of prematurity. In time, increased implementation of next-generation genetic testing in ASD15 will offer opportunities to understand such pathways, and studies of premature infants may yield unique opportunities for investigating the developmental emergence of ASD.

Three decades of ASD genetics: building a foundation for neurobiological understanding and treatment.

Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASDs) for which microarrays, whole exome sequencing and whole genome sequencing have yielded over a hundred causal loci. Genome-wide association studies in ASD have also been fruitful, identifying 5 genome-wide significant loci thus far and demonstrating a substantial role for polygenic inherited risk. Approaches rooted in systems biology and functional genomics have increasingly placed genes implicated by risk variants into biological context. Genetic risk affects a finite group of cell-types and biological processes, converging primarily on early stages of brain development (though, the expression of many risk genes persists through childhood). Coupled with advances in stem cell-based human in vitro model systems, these findings provide a basis for developing mechanistic models of disease pathophysiology.

The promise of precision medicine in autism

Autism spectrum disorder (ASD) is a clinically and etiologically diverse developmental condition characterized by diminished social interactions, impaired communication, and repetitive and/or restrictive behaviors. Recent advances in ASD genetics pave the way for implementation of precision medicine in clinical management of autism.

The Genetics of Autism Spectrum Disorder- A Review

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders representing deficits in socialization, communication impairment, repetitive patterns of behaviors and/or restricted interest. The increasing prevalence of ASD worldwide is most likely due to increasing awareness, widening of the diagnostic concepts and availability of diagnostic framework. It is a genetically influenced disorders caused by factors including genetic, epigenetic factors that affect gene expression and activity and non-genetic factors like environmental exposures. It is widely thought to represent a disorder of connectivity, in which the environment interacts with the genome. It can occur as an association with genetic syndrome, can occur sporadically or may be familial. Recognizing various phenotypic manifestations, it is understood that the underlying etiology of ASD is complex and genetic factors play an important role. The most significant advance in autism biology over the last decade has been in understanding the genetics of autism. The genetic diagnosis can benefit patients and the family by providing information, psychological support both immediate and long term and also can guide and help to prepare for the future. So, genetic diagnosis of ASD may offer opportunities for the identification of molecular targets for novel interventions, and provide new insight for families seeking genetic counseling.&#x0D; J Bangladesh Coll Phys Surg 2021; 39(3): 193-199

Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms.

Recent progress in the identification of genes and genomic regions contributing to autism spectrum disorder (ASD) has had a broad impact on our understanding of the nature of genetic risk for a range of psychiatric disorders, on our understanding of ASD biology, and on defining the key challenges now facing the field in efforts to translate gene discovery into an actionable understanding of pathology. While these advances have not yet had a transformative impact on clinical practice, there is nonetheless cause for real optimism: reliable lists of risk genes are large and growing rapidly; the identified encoded proteins have already begun to point to a relatively small number of areas of biology, where parallel advances in neuroscience and functional genomics are yielding profound insights; there is strong evidence pointing to mid-fetal prefrontal cortical development as one nexus of vulnerability for some of the largest-effect ASD risk genes; and there are multiple plausible paths forward toward rational therapeutics development that, while admittedly challenging, constitute fundamental departures from what was possible prior to the era of successful gene discovery.

Exons as units of phenotypic impact for truncating mutations in autism.

Autism spectrum disorders (ASD) are a group of related neurodevelopmental diseases displaying significant genetic and phenotypic heterogeneity. Despite recent progress in understanding ASD genetics, the nature of phenotypic heterogeneity across probands remains unclear. Notably, likely gene-disrupting (LGD) de novo mutations affecting the same gene often result in substantially different ASD phenotypes. Nevertheless, we find that truncating mutations affecting the same exon frequently lead to strikingly similar intellectual phenotypes in unrelated ASD probands. Analogous patterns are observed for two independent proband cohorts and several other important ASD-associated phenotypes. We find that exons biased toward prenatal and postnatal expression preferentially contribute to ASD cases with lower and higher IQ phenotypes, respectively. These results suggest that exons, rather than genes, often represent a unit of effective phenotypic impact for truncating mutations in autism. The observed phenotypic patterns are likely mediated by nonsense-mediated decay (NMD) of splicing isoforms, with autism phenotypes usually triggered by relatively mild (15-30%) decreases in overall gene dosage. We find that each ASDgene with recurrent mutations can be characterized by a parameter, phenotype dosage sensitivity (PDS), which quantifies the relationship between changes in a gene's dosage and changes in a given disease phenotype. We further demonstrate analogous relationships between exonLGDs and gene expressionchanges in multiplehuman tissues. Therefore, similar phenotypic patterns may be also observed in other human genetic disorders.

Decreased amplitude and reliability of odor-evoked responses in two mouse models of autism.

Sensory processing deficits are increasingly recognized as core symptoms of autism spectrum disorders (ASDs). However the molecular and circuit mechanisms that lead to sensory deficits are unknown. We show that two molecularly disparate mouse models of autism display similar deficits in sensory-evoked responses in the mouse olfactory system. We find that both Cntnap2- and Shank3-deficient mice of both sexes exhibit reduced response amplitude and trial-to-trial reliability during repeated odor presentation. Mechanistically, we show that both mouse models have weaker and fewer synapses between olfactory sensory nerve (OSN) terminals and olfactory bulb tufted cells and weaker synapses between OSN terminals and inhibitory periglomerular cells. Consequently, deficits in sensory processing provide an excellent candidate phenotype for analysis in ASDs.NEW & NOTEWORTHY The genetics of autism spectrum disorder (ASD) are complex. How the many risk genes generate the similar sets of symptoms that define the disorder is unknown. In particular, little is understood about the functional consequences of these genetic alterations. Sensory processing deficits are important aspects of the ASD diagnosis and may be due to unreliable neural circuits. We show that two mouse models of autism, Cntnap2- and Shank3-deficient mice, display reduced odor-evoked response amplitudes and reliability. These data suggest that altered sensory-evoked responses may constitute a circuit phenotype in ASDs.

Systematic phenomics analysis of autism-associated genes reveals parallel networks underlying reversible impairments in habituation

A major challenge facing the genetics of autism spectrum disorders (ASDs) is the large and growing number of candidate risk genes and gene variants of unknown functional significance. Here, we used Caenorhabditis elegans to systematically functionally characterize ASD-associated genes in vivo. Using our custom machine vision system, we quantified 26 phenotypes spanning morphology, locomotion, tactile sensitivity, and habituation learning in 135 strains each carrying a mutation in an ortholog of an ASD-associated gene. We identified hundreds of genotype-phenotype relationships ranging from severe developmental delays and uncoordinated movement to subtle deficits in sensory and learning behaviors. We clustered genes by similarity in phenomic profiles and used epistasis analysis to discover parallel networks centered on CHD8•chd-7 and NLGN3•nlg-1 that underlie mechanosensory hyperresponsivity and impaired habituation learning. We then leveraged our data for in vivo functional assays to gauge missense variant effect. Expression of wild-type NLG-1 in nlg-1 mutant C. elegans rescued their sensory and learning impairments. Testing the rescuing ability of conserved ASD-associated neuroligin variants revealed varied partial loss of function despite proper subcellular localization. Finally, we used CRISPR-Cas9 auxin-inducible degradation to determine that phenotypic abnormalities caused by developmental loss of NLG-1 can be reversed by adult expression. This work charts the phenotypic landscape of ASD-associated genes, offers in vivo variant functional assays, and potential therapeutic targets for ASD.

A perturbed gene network containing PI3K-AKT, RAS-ERK and WNT-β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity.

Hundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1–4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.

Recent genetic and functional insights in autism spectrum disorder

Recent advances in genetic technologies allowed researchers to identify large numbers of candidate risk genes associated with autism spectrum disorder (ASD). Both strongly penetrant rare variants and the accumulation of common variants with much weaker penetrance contribute to the cause of ASD. To identify the highly confident candidate genes, software and resources have been applied, and functional evaluation of the variants has provided further insights for ASD pathophysiology. These studies ultimately identify the molecular and circuit alteration underlying the behavioral abnormalities in ASD. In this review, we introduce the recent genetic and genomic findings and functional approaches for ASD variants providing a deeper understanding of the etiology of ASD. Integrated meta-analysis that recruited a larger number of ASD cases has helped to prioritize ASD candidate genes or genetic loci into highly confidence candidate genes for further investigation. Not only coding but also noncoding variants have been recently implicated to confer the risk of ASD. Functional approaches of genes or variants revealed the disruption of specific molecular pathways. Further studies combining ASD genetics and genomics with recent techniques in engineered mouse models show molecular and circuit mechanisms underlying the behavioral deficits in ASD. Advances in ASD genetics and the following functional studies provide significant insights into ASD pathophysiology at molecular and circuit levels.