The autism spectrum disorders (ASDs) are a group of conditions typically characterized by repetitive behaviour, severely restricted interests and difficulties with social interactions and communication. ASDs are highly heritable, yet the underlying genetic determinants remain largely unknown. A genome-wide analysis reveals that people with ASDs carry a higher load of rare copy-number variants — segments of DNA for which the copy number differs between individual genomes — which are either inherited or arise de novo. The results implicate several novel genes as ASD candidates and point to the importance of cellular proliferation, projection and motility as well as specific signalling pathways in this disorder. The autistic spectrum disorders (ASDs) are highly heritable, yet the underlying genetic determinants remain largely unknown. Here, a genome-wide analysis of rare copy number variants (CNVs) has been carried out, revealing that ASD sufferers carry a higher load of rare, genic CNVs than do controls. Many of these CNVs are de novo and inherited. The results implicate several novel genes in ASDs, and point to the importance of cellular proliferation, projection and motility, as well as specific signalling pathways, in these disorders. The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable (∼90%)3, the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Background: Mortality has been suggested to be increased in autism spectrum disorder (ASD).Aims: To examine both all-cause and cause-specific mortality in ASD, as well as investigate moderating role of gender and intellectual ability.Method: Odds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27 122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2 672 185).Results: During the observed period, 24 358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38–2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability.Conclusions: Premature mortality was markedly increased in ASD owing to a multitude of medical conditions.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10⁻⁸. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10⁻⁸ threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Autism spectrum disorder (ASD) is a neurodevelopmental condition of heterogeneous etiology. While it is widely recognized that genetic and environmental factors and their interactions contribute to autism phenotypes, their precise causal mechanisms remain poorly understood. This article reviews our current understanding of environmental risk factors of ASD and their presumed adverse physiological mechanisms. It comprehensively maps the significance of parental age, teratogenic compounds, perinatal risks, medication, smoking and alcohol use, nutrition, vaccination, toxic exposures, as well as the role of extreme psychosocial factors. Further, we consider the role of potential protective factors such as folate and fatty acid intake. Evidence indicates an increased offspring vulnerability to ASD through advanced maternal and paternal age, valproate intake, toxic chemical exposure, maternal diabetes, enhanced steroidogenic activity, immune activation, and possibly altered zinc–copper cycles and treatment with selective serotonin reuptake inhibitors. Epidemiological studies demonstrate no evidence for vaccination posing an autism risk. It is concluded that future research needs to consider categorical autism, broader autism phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification. Our understanding of autism etiology could be advanced by research aimed at disentangling the causal and non-causal environmental effects, both founding and moderating, and gene–environment interplay using twin studies, longitudinal and experimental designs. The specificity of many environmental risks for ASD remains unknown and control of multiple confounders has been limited. Further understanding of the critical windows of neurodevelopmental vulnerability and investigating the fit of multiple hit and cumulative risk models are likely promising approaches in enhancing the understanding of role of environmental factors in the etiology of ASD.