De novo mutations identified by whole-genome sequencing implicate chromatin modifications in obsessive-compulsive disorder.

Abstract

Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder with a substantial genetic basis and a broadly undiscovered etiology. Recent studies of de novo mutation (DNM) exome-sequencing studies for OCD have reinforced the hypothesis that rare variation contributes to the risk. We performed, to our knowledge, the first whole-genome sequencing on 53 parent-offspring families with offspring affected with OCD to investigate all rare de novo variants and insertions/deletions. We observed higher mutation rates in promoter-anchored chromatin loops (empirical <i>P</i> = 0.0015) and regions with high frequencies of histone marks (empirical <i>P</i> = 0.0001). Mutations affecting coding regions were significantly enriched within coexpression modules of genes involved in chromatin modification during human brain development. Four genes—<i>SETD5</i>, <i>KDM3B</i>, <i>ASXL3</i>, and <i>FBL</i>—had strong aggregated evidence and functionally converged on transcription’s epigenetic regulation, suggesting an important OCD risk mechanism. Our data characterized different genome-wide DNMs and highlighted the contribution of chromatin modification in the etiology of OCD.