SummaryThe genetic architecture of autism spectrum disorder involves the interplay of common and rare variation and their impact on hundreds of genes. Using exome sequencing, analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, and a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic, transcriptional, and chromatin remodeling pathways. These include voltage-gated ion channels regulating propagation of action potentials, pacemaking, and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodelers, prominently histone post-translational modifications involving lysine methylation/demethylation.

No abstract

Highlights d 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR % 0.1) d Most are expressed and enriched early in excitatory and inhibitory neuronal lineages d Most affect synapses or regulate other genes; how these roles dovetail is unknown d Some ASD genes alter early development broadly, others appear more specific to ASD

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1 -4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5 -9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11 , 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10 −3 ). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10 −3 ). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10 −6 ). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.ASDs, including autism, are neurodevelopmental disorders characterized by impairments in social and communication skills, as well as stereotyped and repetitive behaviours and/or a restricted range of interests. Current prevalence estimates in the United States are 0.1-0.2% for autism and 0.6% for ASDs 1,2 .Linkage and candidate gene association studies have implicated several chromosomal regions in autism 3,4 . However, positive findings in one study often fail to replicate in other studies, and a consistent picture of susceptibility loci in autism is still lacking. Some telling clues about ASD genetics arose from recent studies on CNVs 5 , including the association of de novo CNVs with ASDs 6 . Although de novo CNVs that disrupt specific genes may contribute to the pathogenesis of ASDs, heritable CNVs are much more common but have been less studied as risk factors of ASDs. A family-based genome-wide linkage and CNV analysis by the Autism Genome Project Consortium using Affymetrix 10K single nucleotide polymorphism (SNP) arrays implicated chromosome 11p12-13 and neurexin 1 (NRXN1) as candidate loci 7 . A study using the Affymetrix 500K SNP array in a Canadian population reported 277 rare CNVs that were only observed in ASD patients but not in 1,652 healthy controls or in the Database of Genomic Variants 8 . Furthermore, 16p11.2 deletions and Glessner et al.Page 2 Nature. Author manuscript; available in PMC 2010 August 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscri...

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn’s disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.