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Joseph Buxbaum and colleagues use an epidemiological sample from Sweden to investigate the genetic architecture of autism spectrum disorders. They conclude that most inherited risk for autism is determined by common variation and that rare variation explains a smaller fraction of total heritability. A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse 9 , 10 . At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)—a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7–64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

Key Points Over the past 5 years, researchers have identified many genetic factors that increase the risk of autism spectrum disorder (ASD), and that might shed light on more-homogeneous subgroups within the spectrum The most robustly identified genetic risks for ASD are rare mutations with large effect; studies have been underpowered to detect common genetic variation The role of rare genetic variants supports the relevance of studying monogenic disorders, such as tuberous sclerosis complex, for understanding ASD pathophysiology The most parsimonious explanation for the male predominance in ASD involves the presence of protective factors that reduce the risk of ASD in females Many genetic mutations associated with ASD also confer high risk of comorbidities including epilepsy, motor impairment and sleep disturbance Genetic testing including chromosomal microarray analysis is warranted and clinically indicated for all suspected cases of ASD Considerable phenotypic and genetic heterogeneity exists among the neurodevelopmental disorders described by the term autism spectrum disorder (ASD), which presents a challenge to treatment. Shafali and Geschwind outline the latest advances in genetic methods to identify and detect ASD-associated variants, and consider three themes—single-gene disorders, the gender bias in ASD, and neurological comorbidites—that could enable improved definition of ASD subgroups and understanding of disease aetiology. Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment.

Key Points Autism is a neurodevelopmental disorder that is diagnosed by the presence of three categories of behavioural criteria: first, unusual reciprocal social interactions; second, deficits in communication; and third, stereotyped, repetitive behaviours with restricted interests. Behavioural phenotyping of mouse models of autism requires assays that are relevant to each of the three categories of the core symptoms. Optimal animal models incorporate phenotypes that are analogous to the human disease (face validity). They should also incorporate the same cause as the human disease (construct validity), and ameliorative responses that are specific to treatments that are efficacious in the human disease (predictive validity). Robust phenotypes in mouse models of autism that have face validity and construct validity hold great promise as translational tools for discovering effective therapeutics for components of autism spectrum disorders. Mus musculus is a social species that engages in high levels of reciprocal social interactions. Assays for deficits in sociability include the three-chambered social approach test, the partition test, observer-scored parameters of reciprocal social interactions and tests of social transmission of food preference. Communication in mice is not well understood, but assays to investigate this include olfactory discrimination, urinary scent marking and countermarking, and assays of ultrasonic vocalizations in social settings. Assays for repetitive behaviours and restricted interests in mice include measures of motor stereotypies, repetitive self-grooming and perseverative spatial habits in learning tasks that include the T-maze and Morris water maze. Control parameters that assess general health, motor functions and sensory abilities (for example, olfactory detection of pheromones) are essential for ruling out artefacts that could confound the interpretation of social, communication or repetitive phenotypes. The diagnosis of autism is based on behavioural criteria. Robust phenotypes in mouse models hold great promise for the discovery of effective treatments for the core symptoms of autism spectrum disorders. Crawley and colleagues review the behavioural assays that are most relevant to the symptoms of human autism, along with the essential control measures. Autism is a heterogeneous neurodevelopmental disorder of unknown aetiology that affects 1 in 100–150 individuals. Diagnosis is based on three categories of behavioural criteria: abnormal social interactions, communication deficits and repetitive behaviours. Strong evidence for a genetic basis has prompted the development of mouse models with targeted mutations in candidate genes for autism. As the diagnostic criteria for autism are behavioural, phenotyping these mouse models requires behavioural assays with high relevance to each category of the diagnostic symptoms. Behavioural neuroscientists are generating a comprehensive set of assays for social interaction, communication and repetitive behaviours to test hypotheses about the causes of austism. Robust phenotypes in mouse models hold great promise as translational tools for discovering effective treatments for components of autism spectrum disorders.

Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of postmortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex and cerebellum. We measured over 485 000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified four genome-wide significant differentially methylated regions (DMRs) using a bump hunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2 +/− and Fmr1 −/y mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments. The mutations that underlie the diseases tuberous sclerosis complex and fragile X syndrome produce abnormalities in synaptic plasticity and function that can be corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions. Contrasting mutants linked to autism Recent studies suggest that autism spectrum disorder and associated intellectual disability may arise from altered plasticity and function of synapses in the brain. This is exemplified by a series of experiments on mice carrying the single gene defects associated with tuberous sclerosis complex and fragile X syndrome, two genetic diseases characterized by intellectual disability and autism. Both mutations are associated with altered protein synthesis in neurons, so it was expected that similar treatments would be beneficial in both. However, synaptic dysfunction and cognitive deficits caused by these mutations are corrected by treatments that modulate metabotropic glutamate receptor 5 (mGluR 5) in opposite directions, and the effects of the two mutations cancel each other when introduced simultaneously. This suggests that the two mutations can cause similar dysfunction by deviating from an optimal range of mGluR-mediated activity in opposite directions.

Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. Other strengths of the cohort included nearly complete ascertainment of pregnancies in Finland ( N =1.2 million) over the study period and national psychiatric registries consisting of virtually all treated autism cases in the population. Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared with the lowest quintile, there was a significant, 43% elevated risk. This finding suggests that maternal inflammation may have a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders.

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

Purpose: Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care. Methods: A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions. Results: Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. Conclusion: Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.

Despite increasing evidence of oxidative stress in the pathophysiology of autism, most studies have not evaluated biomarkers within specific brain regions, and the functional consequences of oxidative stress remain relatively understudied. We examined frozen samples from the cerebellum and temporal cortex (Brodmann area 22 (BA22)) from individuals with autism and unaffected controls ( n =15 and n =12 per group, respectively). Biomarkers of oxidative stress, including reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione redox/antioxidant capacity (GSH/GSSG), were measured. Biomarkers of oxidative protein damage (3-nitrotyrosine; 3-NT) and oxidative DNA damage (8-oxo-deoxyguanosine; 8-oxo-dG) were also assessed. Functional indicators of oxidative stress included relative levels of 3-chlorotyrosine (3-CT), an established biomarker of a chronic inflammatory response, and aconitase activity, a biomarker of mitochondrial superoxide production. Consistent with previous studies on plasma and immune cells, GSH and GSH/GSSG were significantly decreased in both autism cerebellum ( P <0.01) and BA22 ( P <0.01). There was a significant increase in 3-NT in the autism cerebellum and BA22 ( P <0.01). Similarly, 8-oxo-dG was significantly increased in autism cerebellum and BA22 ( P <0.01 and P =0.01, respectively), and was inversely correlated with GSH/GSSG in the cerebellum ( P <0.01). There was a significant increase in 3-CT levels in both brain regions ( P <0.01), whereas aconitase activity was significantly decreased in autism cerebellum ( P <0.01), and was negatively correlated with GSH/GSSG ( P =0.01). Together, these results indicate that decreased GSH/GSSG redox/antioxidant capacity and increased oxidative stress in the autism brain may have functional consequence in terms of a chronic inflammatory response, increased mitochondrial superoxide production, and oxidative protein and DNA damage.