A genome-wide association study (GWAS) of 18,381 autism spectrum disorder (ASD) cases and 27,969 controls identified five genome-wide significant loci associated with ASD. The study also identified seven additional loci shared with other traits, including schizophrenia, major depression, and educational attainment. The results highlight biological insights, particularly related to neuronal function and corticogenesis, and demonstrate that GWAS performed at scale will be more productive in the near term for ASD research. The study found quantitative and qualitative polygenic heterogeneity across ASD subtypes, indicating differences in genetic architecture among subtypes. The results also showed strong genetic correlations between ASD and other complex disorders and traits, confirming shared etiology. The study leveraged computational techniques to identify additional novel ASD-associated variants shared with other phenotypes. Functional annotation of the GWAS results revealed enrichment in conserved DNA regions and histone marks, as well as genes expressed in central nervous system cell types. The study also identified credible SNPs associated with brain development and neuronal function, including those in the developing brain, germinal matrix, cortex-derived neurospheres, and embryonic stem cell-derived neurons. The results suggest that common genetic variants contribute significantly to ASD susceptibility, and that the genetic architecture of ASD is complex and heterogeneous. The study also found that the contribution of common variants may be more prominent in high-functioning ASD cases such as Asperger's syndrome. The study used a multi-phenotype PRS approach to improve prediction of ASD, demonstrating that individual ASD risk depends on the level of polygenic burden of thousands of common variants in a dose-dependent way. The study also found that the genetic architecture underlying educational attainment is shared with ASD but to a variable degree across the disorder spectrum. The results provide important insights into the genetic basis of ASD and its relationship with other complex disorders and traits.A genome-wide association study (GWAS) of 18,381 autism spectrum disorder (ASD) cases and 27,969 controls identified five genome-wide significant loci associated with ASD. The study also identified seven additional loci shared with other traits, including schizophrenia, major depression, and educational attainment. The results highlight biological insights, particularly related to neuronal function and corticogenesis, and demonstrate that GWAS performed at scale will be more productive in the near term for ASD research. The study found quantitative and qualitative polygenic heterogeneity across ASD subtypes, indicating differences in genetic architecture among subtypes. The results also showed strong genetic correlations between ASD and other complex disorders and traits, confirming shared etiology. The study leveraged computational techniques to identify additional novel ASD-associated variants shared with other phenotypes. Functional annotation of the GWAS results revealed enrichment in conserved DNA regions and histone marks, as well as genes expressed in central nervous system cell types. The study also identified credible SNPs associated with brain development and neuronal function, including those in the developing brain, germinal matrix, cortex-derived neurospheres, and embryonic stem cell-derived neurons. The results suggest that common genetic variants contribute significantly to ASD susceptibility, and that the genetic architecture of ASD is complex and heterogeneous. The study also found that the contribution of common variants may be more prominent in high-functioning ASD cases such as Asperger's syndrome. The study used a multi-phenotype PRS approach to improve prediction of ASD, demonstrating that individual ASD risk depends on the level of polygenic burden of thousands of common variants in a dose-dependent way. The study also found that the genetic architecture underlying educational attainment is shared with ASD but to a variable degree across the disorder spectrum. The results provide important insights into the genetic basis of ASD and its relationship with other complex disorders and traits.