Most genetic risk for autism reflects the aggregate activity of thousands of common genetic differences distributed throughout the genome. This is typically referred to as common polygenic risk, and it is likely to influence distinct and important components of autism biology. In this application, Elise Robinson and olleagues propose a group of activities to unlock autism’s polygenic influences.

Following a July 2025 addition of several thousand autism genomes to the Psychiatric Genomics Consortium (PGC) GWAS effort, there was a rapid increase in GWAS locus identification. This suggests that the autism GWAS has reached an “inflection point”, a sample size after which common variant associations are identified more quickly. Together with the PGC, the Robinson lab will further advance the increasingly generative autism GWAS through the incorporation of all new data released from SPARK, the Autism Inpatient Collection, the NeuroDev project and other new data.

The GWAS meta-analysis of this resource will identify new common variants associated with autism, identify the polygenic risk scoring approach that produces the strongest autism polygenic score, and query cohort-level heterogeneity. Using the improved common variant signature, the Robinson lab will examine the impacts of cell type, tissue type, developmental stage, and genomic region on the biological consequences of common polygenic risk for autism. Using several recently developed approaches, and eQTL resources from PsychENCODE, GTEx, and CommonMind, they will map the functional impact of common polygenic risk for autism across human tissues, examine variability in the functional impact of polygenic risk for autism across brain cell types, and compare the functional consequence of common polygenic risk for neuropsychiatric disease between fetal and adult brain tissue. These activities will characterize autism’s common polygenic architecture and uncover the functional consequences of autism-associated polygenic variation.