Rare variation illuminates the distinct and pleiotropic genetic architecture of autism across neuropsychiatric traits

Abstract

Autism spectrum disorder is a heritable neurodevelopmental condition affecting approximately 3% of children1,2 that presents with core behavioral features and a range of possible comorbidities, including intellectual disability3. While common variants contribute substantially to autism liability4, the discovery of specific autism-associated genes has largely been driven by studies of rare and de novo variants5. Many of these genes are also linked with broadly defined developmental disorders5,6, but their involvement in other conditions has not been mapped at scale. Here, we analyze autosomal rare coding variation from 62,429 individuals with autism from research and clinical cohorts to identify 253 autism-associated genes at an estimated false discovery rate < 0.001. We cluster them based on association evidence from large-scale studies of developmental disorders, schizophrenia, bipolar disorder, and epilepsy, generating six clusters of genes with differing biological pathway enrichments and patterns of comorbidities. Investigating rare variant associations in the population using the UK Biobank and All of Us, we identify autism-associated genes displaying pleiotropy across physiological systems. In addition, we report 497 genes impacting development in a meta-analysis with 26,109 published developmental disorders samples. Collectively drawing upon data from over 1.5 million individuals, our study finds that rare variants across hundreds of genes contribute to autism with variable phenotypic outcomes.