ADVANCING OUR UNDERSTANDING OF THE GENETICS OF AUTISM: FINDINGS FROM THE LARGEST GWAS TO DATE

Background Autism spectrum disorder is a neurodevelopmental condition characterised by difficulties in social interaction and communication, alongside repetitive and stereotyped behaviours. Prevalence estimates now exceed 1% worldwide. Although autism is highly heritable, with estimates around 80%, the genetic architecture has long remained elusive. Recent progress—particularly in the study of rare and de novo variants—has identified more than 250 autism associated genes. However, advances in understanding the contribution of common variants have been comparatively slow. Here, we report results from the new publication freeze of the Psychiatric Genomics Consortium (PGC) and iPSYCH-Broad autism GWAS, covering both autosomal and X chromosomal analyses. Methods Most cohorts were processed using the PGC Ricopili pipeline and imputed to the HRC reference panel. Additional cohorts were harmonised and aligned to comparable standards. Cohort-level GWAS summary statistics were combined using inverse-variance weighted meta-analysis. SNP-based heritability was estimated using LDAK and LDSC; genetic correlations were assessed using LDSC, MiXeR, and LAVA. Polygenic scores were derived with SBayesR in LDAK. Functional enrichment was evaluated using MAGMA and LDSC, and GWAS findings were integrated with single-cell RNA seq data via scDRS and with spatial transcriptomics via gsMap. Results In a meta-analysis of 46,930 autism cases and 255,848 controls, we identified 23 distinct genome wide significant loci associated with autism. Of the three loci previously reported in our 2019 GWAS, two replicate at genome wide significance, whereas one is absent from the HRC reference panel used here. Overall, the results show strong concordance with earlier findings at both the locus and polygenic levels. At the conference, we will quantify convergence between these common variant results and the latest rare variant discoveries from the Autism Sequencing Consortium, dissect the heterogeneity across ICD10 diagnostic subgroups, and present functional and spatial interpretations of the of the GWAS results. Discussion This new PGC3–ASD GWAS identifies > 4 times more loci than the previous GWAS and provides a far stronger foundation for biological inference. Despite this progress, autism GWAS power remains limited compared with other major psychiatric disorders. Expanding sample size—particularly across underrepresented ancestries—remains a critical priority for future discovery.