Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture, we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD.

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

A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (henceforth autism) the nature of its allelic spectrum is uncertain. Individual risk genes have been identified from rare variation, especially de novo mutations1–8. From this evidence one might conclude that rare variation dominates its allelic spectrum, yet recent studies show that common variation, individually of small effect, has substantial impact en masse9,10. At issue is how much of an impact relative to rare variation. Using a unique epidemiological sample from Sweden, novel methods that distinguish total narrow-sense heritability from that due to common variation, and by synthesizing results from other studies, we reach several conclusions about autism’s genetic architecture: its narrow-sense heritability is ≈54% and most traces to common variation; rare de novo mutations contribute substantially to individuals’ liability; still their contribution to variance in liability, 2.6%, is modest compared to heritable variation.

SummaryWe 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.

Importance Autism Spectrum Disorders (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors, or shared or non-shared environment remains unresolved. Objective To provide estimates of familial aggregation of ASD. Design, Setting and Participants A population based cohort of all Swedish children born 1982–2007. We identified all twins, full siblings, maternal and paternal half siblings and cousin pairs and all diagnosis of ASD to 31-December-2009. Main Outcome Measure(s) The relative recurrence risk (RR) measure familial aggregation of disease. The RR is the relative risk of autism in an participant given a sibling or cousin has the diagnosis, compared with the risk in a participant with no diseased family member. We calculated RR for both ASD and Autistic Disorder (AD). We estimated how much of the probability of developing ASD can be related to genetic (additive and dominance) and environmental (shared and non-shared) factors. Results In the sample of 2,049,899 children, 14,516 obtained an ASD diagnosis of which 5,689 were AD. The ASD RR was estimated to 153.0 (95%CI 56.7–412.8; 27 vs 6,273 per 100,000 person-years) for monozygotic twins, 8.2 (95%CI 3.7–18.1; 55 vs 805 per 100,000 person-years) for dizygotic twins, 10.3 (95%CI 9.4–11.2; 49 vs 829 per 100,000 person-years) for full-siblings, 3.3 (95%CI 2.6–4.2; 94 vs 492 per 100,000 person-years) for maternal half siblings, 2.9 (95%CI: 2.2–3.7; 85 vs 371 per 100,000 person-years) for paternal half siblings, and 2.0 (95%CI: 1.8–2.2; 49 vs 155 per 100,000 person-years) for cousins. The RR pattern was similar for AD but of slightly higher magnitude. We found support for a disease etiology including only additive genetic and non-shared environmental effects. The ASD heritability was estimated to 0.50 (95%CI 0.44–0.55) and the AD heritability was estimated to 0.54 (95%CI 0.44–0.64). Conclusion and Relevance Among children born in Sweden, heritability of ASD and AD were estimated to be approximately 50%. For an individual, the risk of autism is increased 10 fold if a full sibling has the diagnosis and about 2 fold if a cousin has the diagnosis. These findings may inform counseling families with affected children.

Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Author Contributions: Drs Sandin and Kuja-Halkola had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.