Learning biology from common and rare variant associations to autism

Autism is associated with a broad spectrum of genetic factors, from rare variants that severely disrupt neurodevelopment to thousands of common variants whose effects are subtle individually but important in aggregate. Strong impact mutations provide clear starting points for biological research, but they are observed in only a minority of autistic individuals. By contrast, common polygenic influences are relevant to virtually all autism patient groups, but have been difficult to query biologically. To understand the biology of autism, it is necessary to improve our understanding of both lines of evidence and to identify the genes, pathways and developmental processes on which they converge. In this symposium, we present 2023’s autism association updates - including a new PGC Autism freeze - along with collaborative work to better characterize heterogeneity in autism's genetic architecture. We then introduce projects interrogating the functional impact of autism-associated genetic variation, integrating the new common and rare variant signals, and learning biology from polygenicity. Dr. Susan Kuo will begin the symposium by introducing the current state of autism association studies. She will then present a new algorithm that uses clinical information (e.g. age of walking) to stratify the probability with which an autistic child carries a rare, neurodevelopmental disorder associated genetic variant. Dr. Kuo will introduce a new web resource that makes individually estimated probabilities available to clinicians and families of autistic children, and aims to clearly describe autism genetics - and autism heterogeneity - to the public. Second, Dr. Lucy Bicks will present new approaches to understanding the biological mechanisms implied by autism GWAS loci, and describe the specific cell types and co-expression modules impacted by those loci in human brain. He will present his group's integration of autism-associated common genetic variation into protein-protein interaction networks developed from rare variant studies, and query whether autism's common and rare variant influences impact similar pathways and transcriptional regulatory networks. Third, Dr. Anna Starnawska will describe new insights into DNA methylation (DNAm) associations to autism. She will present an epigenome-wide association study (EWAS) of ASD which identifies differential DNAm between 843 cases and 688 population controls, and an EWAS of the polygenic score for autism, which identifies DNAm changes associated with polygenic influences on the diagnosis. Lastly, she will present a methylation Quantitative Trait Loci (mQTL) analysis which identifies the impact of common, autism associated variants on epigenetic regulation. Finally, Dr. Georgios Voloudakis will present work to understand results from the new PGC autism freeze, leveraging large-scale, high resolution multi-omics datasets derived from brain homogenate, FANS/FACS-sorted cells/nuclei and single-nucleus data. The project prioritizes putatively causal SNPs associated with changes in transcriptomes and chromatin accessibility, performs a transcriptome-wide association study to identify autism-associated transcripts and biological pathways, and identifies cell subtypes exhibiting high expression across ASD-associated genes.