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We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Background Studies of de novo variation, which is identified by exome sequencing parent-offspring families, have successfully identified over 100 genes associated with neurodevelopmental disorders, most notably intellectual disability / developmental delay (ID/DD) or autism spectrum disorders (ASDs). Mutations in the genes first discovered in de novo studies of ASD were specifically enriched in those ASD individuals with comorbid ID/DD, and these genes were commonly assumed to affect both traits. As such, some criticized these studies for failing to separate ID/DD genes from those genes that confer risk to ASD without ID/DD. Winner's curse suggests the effect size for these genes would be greatest in ASD (i.e., the trait it was first discovered in). Through a meta-analysis of de novo variants from 3982 probands ascertained for ASD (892 with comorbid ID/DD) and 5264 probands ascertained for ID/DD (503 with comorbid ASD) we show that, in fact, the reverse is true: previously associated ASD genes are more often mutated in individuals with ID/DD who do not have ASD. Methods We meta-analyzed of 14,048 previously published de novo variants from 9,246 families (father, mother, affected proband). We leveraged detailed phenotyping on 85.9% of the probands to increase power to both identify associated genes and calculate the degree of risk each gene confers for different disorders. Results To identify disease associated genes, we compared the number of observed de novo missense and protein-truncating variants (PTVs) to the number expected from a null mutational model across three sets: ASD+ID/DD, ASD only, and ID/DD only. This yielded a total of 98 significant genes, 8 of which are novel. The contribution of evidence towards each gene's association is overwhelmingly provided by ID/DD compared to ASD (4.9-fold excess; P Discussion Studying de novo variation has been extremely successful for identifying disease-associated genes, with ASD being arguably the flagship trait for this study design. However, the presence of comorbid ID/DD in ASD probands with associated de novo variants begged the question as to how much risk each gene confers to the different disorders. Leveraging detailed phenotyping in a meta-analysis of 3982 ASD and 5264 ID/DD individuals, we identified 98 disease-associated genes, of which only 3 are more strongly associated with ASD than ID/DD. Furthermore, genes previously associated with ASD are more often observed in individuals with ID/DD who themselves do not have ASD. Therefore, researchers should be cautious with using published lists of ASD genes for follow-up functional studies - especially if the goal is to learn about the genetic etiology of core ASD features in the absence of cognitive impairment - namely social and behavioral impairments.

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1). Through analysis of de novo mutations in autism spectrum disorder (ASD), Sanders et al. find that small deletions, but not large deletions/duplications, contain one critical gene. Combining CNV and sequencing data, they identify 6 loci and 65 genes associated with ASD.