Alterations in chromatin accessibility and conformation elucidate genetic mechanisms in ASD

Genetic risk for psychiatric disorders lies largely within non-coding regions, where the lack of detailed knowledge of gene regulation and chromatin structure has hampered understanding of disease mechanisms. We analyzed chromatin accessibility and 3D genome architecture in brains from 53 ASD and neurotypical individuals, including patients with (dup) 15q11-13. We observed reduced CTCF binding, which had dual effects: a) decreased chromatin accessibility at distal enhancers and downregulation of synaptic and neuronal target genes, and b) weakened TAD boundaries linked to DNA hypermethylation, impacting a distinct set of genes. These changes were associated with brain mQTLs, caQTLs, and rare variants increasing ASD risk, a subset of which we validated by CRISPR editing, supporting a causal relationship. Our analyses suggest that genetic variants contribute to risk in part through a combination of epigenetic changes, including disruption of distal enhancer accessibility and 3D genome organization in both idiopathic and a syndromic form of ASD.