Individuals with autism-associated intellectual disability have an increased burden of de novo variants in cis-regulatory elements of glutamatergic neurons

Despite the trait of autism being strongly heritable, with many genes now implicated in its causation, the ability to make a clinical diagnosis in an affected individual remains limited. In this study, we sought to understand how DNA sequence variation in the non-coding majority of the human genome contributes to autism-associated intellectual disability (ID), We studied whole genome sequencing data from 20,366 individuals, in whom 709,222 de novo variants (DNVs) were identified. We tested the genomic distributions and properties of the DNVs in individuals with autism and ID compared with neurotypical study participants. We found enrichment of DNVs at cis -regulatory elements (CREs) across all somatic cell types in both the neurodivergent and neurotypical groups, attributable to the deamination of 5-methylcytosine at CG dinucleotide-dense CREs. In neurodivergent individuals with or without ID, the DNVs were enriched at genes implicated in autism/ID at promoter-proximal CREs of brain cell types specifically. Since the properties of these DNVs were not distinct enough to explain why some individuals had autism or ID, we performed a multivariate category-wide association study (CWAS), which revealed enrichment of DNVs in CREs of glutamatergic neurons in individuals with ID. A Random Forest analysis uncovered an increased burden of these events in individuals within the ID subgroup. Our findings support a model in which non-coding variants contribute to the oligogenic heritability of ID, through influences on the transcriptional regulation of glutamatergic neurons.