DNA variants affecting chromatin structure are key to the genetic architecture of obsessive compulsive disorder

Obsessive Compulsive Disorder (OCD) affects 2 to 3% of the population and is marked by intrusive thoughts and repetitive behaviours. OCD is increasingly recognized as a polygenic disorder involving gene-environment interactions, with genetic risk largely driven by common variants and a smaller contribution from rare pathogenic variation. Despite these insights, the functional roles of implicated genes remain unclear. Recent genomic studies suggest that chromatin dysregulation contributes to the pathogenesis of OCD.

We analysed the recently published large-scale genome-wide association study meta-analysis of OCD by Strom et al., which included 53,660 cases and over 2 million controls. This study identified 30 genome-wide significant loci and approximately 11,500 common variants, together explaining 90% of OCD heritability. We analysed the 251 prioritized genes mapped through six genomic methods identified in this study. Gene Ontology over representation analysis (ORA) showed enrichment in chromatin-related pathways, including nucleosome assembly and DNA packaging, mainly driven by histone H1 to H4 genes. We also analysed two additional studies, a whole-exome sequencing study involving 1313 cases by Halvorsen et al., and a whole-genome sequencing study involving 53 parent-offspring trios by Lin et al., both of which found an enrichment of chromatin regulation genes in OCD.

Chromatin remodeling regulates neuronal differentiation, synaptic gene expression, and immune signaling. Disruptions in these processes may alter neurotransmission and immune responses, contributing to OCD symptoms and their fluctuation with stress or infection. Our findings highlight chromatin dysregulation as a shared mechanism across common and rare OCD variants. This supports a gene environment model and suggests chromatin remodeling as a novel therapeutic target. Further epigenomic research is needed to investigate these potential mechanisms.