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 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

We present a meta-analysis of studies that compare figurative language comprehension in individuals with autism spectrum disorder and in typically developing controls who were matched based on chronological age or/and language ability. A total of 41 studies and 45 independent effect sizes were included based on predetermined inclusion criteria. Group matching strategy, age, types of figurative language, and cross-linguistic differences were examined as predictors that might explain heterogeneity in effect sizes. Overall, individuals with autism spectrum disorder showed poorer comprehension of figurative language than their typically developing peers (Hedges’ g = –0.57). A meta-regression analysis showed that group matching strategy and types of figurative language were significantly related to differences in effect sizes, whereas chronological age and cross-linguistic differences were not. Differences between the autism spectrum disorder and typically developing groups were small and nonsignificant when the groups were matched based on the language ability. Metaphors were more difficult to comprehend for individuals with autism spectrum disorder compared with typically developing controls than were irony and sarcasm. Our findings highlight the critical role of core language skills in figurative language comprehension. Interventions and educational programmes designed to improve social communication skills in individuals with autism spectrum disorder may beneficially target core language skills in addition to social skills.

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, in contrast to what is typically seen in other complex disorders. 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, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.