Rare coding variation in OCD implicates shared genes with other psychiatric disorders.

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Obsessive-compulsive disorder (OCD) affects 2-3% of the population and has high heritability, yet the role of rare genetic variants remains understudied.
• Genetic studies in OCD have lagged behind other psychiatric disorders, particularly concerning rare genetic variations.

Purpose of the Study:

• To identify rare coding genetic variants associated with OCD risk.
• To investigate the genetic overlap between OCD, chronic tic disorders (CTD), and other psychiatric conditions.

Main Methods:

• Whole-exome sequencing (WES) was conducted on a large sample of 6,071 individuals with OCD and 38,018 controls across 11 international cohorts.
• Rare damaging coding variants were analyzed, with meta-analyses performed using CTD data and gene-set enrichment analyses to evaluate cross-disorder genetic overlap.

Main Results:

• Approximately 470 autosomal genes were estimated to contribute to OCD risk via rare genetic variation.
• CHD8 was identified as the first gene to reach genome-wide significance for OCD risk.
• Significant genetic overlap was observed between OCD and neurodevelopmental conditions such as autism spectrum disorder (ASD) and developmental delay, but not with adult-onset disorders like bipolar disorder or schizophrenia.

Conclusions:

• This study represents the largest investigation to date of rare coding variation in OCD, confirming CHD8 as a significant rare-variant risk gene.
• The findings highlight substantial genetic overlap between OCD and neurodevelopmental conditions, refining the understanding of OCD's developmental framework.
• The results inform future research into the mechanisms and clinical aspects of OCD and related disorders.