Introduction
Autism spectrum disorders (ASDs) affect ∼1% of the population and are characterized by impairments in social interaction and communication, as well as by repetitive and restricted behaviors. ASDs include mild to severe levels of impairment—cognitive function ranges from above average to intellectual disability (ID)—and are often accompanied by seizures and other medical problems. There is a ∼4:1 male-to-female gender ratio in ASD.
ASDs are highly heritable,1 and genomic studies have revealed that a substantial proportion of ASD risk resides in high-impact rare variation, ranging from chromosome abnormalities and copy-number variation (CNV)2–6 to single-nucleotide variation (SNV).7–11 These studies have highlighted a striking degree of genetic heterogeneity, implicating both de novo germline mutation and rare inherited ASD variation distributed across numerous genes. De novo CNVs are observed in 5%–10% of screened ASD-affected individuals, and after further follow-up studies, some of them have proven to alter high-risk genes (e.g., NRXN112 [MIM 600565]). De novo or transmitted CNVs, such as 15q11.2–q13 duplications of the affected region in Prader-Willi syndrome (PWS [MIM 176270]) and Angelman syndrome (AS [MIM 105830]), 16p11.2 deletion (MIM 611913), 16p11.2 duplication (MIM 614671), and X-linked deletions including the PTCHD1-PTCHD1AS locus (MIM 300828), have also been found to contribute to risk.6,13,14 Exome and whole-genome sequencing studies have estimated at least another ∼6% contribution to ASD7–10,15 and an additional 5% conferred by rare inherited recessive or X-linked loss-of-function (LoF) SNVs.11,16 A genetic overlap between ASD and other neuropsychiatric conditions has also been increasingly recognized.
Interestingly, CNV testing and exome sequencing have so far yielded mostly nonoverlapping genes, which might reflect different mutational mechanisms, although they might still perturb connected biological pathways.17 Although numerous ASD-associated loci have been recognized to date,18 they only account for a small fraction of the overall estimated heritability, consistent with predictions that there might be ∼1,000 loci underlying ASD19 and that many associated genes and risk variants remain to be identified.
Here, we have assessed the impact of de novo and inherited rare CNV in 2,446 ASD individuals and their parents from the Autism Genome Project (AGP), along with 2,640 unrelated controls, by applying a series of approaches to characterize candidate ASD-associated genes disrupted by CNVs and to identify the biological relationships and common pathways they share. Using evidence from multiple sources, we were able to directly implicate numerous dosage-sensitive genes as risk factors and provide insights into different but related mechanisms underlying ASD.