Objective:

To identify high-confidence, large-effect risk genes contributing to obsessive-compulsive disorder (OCD) and chronic tic disorders (CTDs).

Approach:

• Study Design: Utilized whole-exome sequencing data from 3,964 patients, including parent-proband trios and singletons, alongside control data from neurotypical sibling-parent trios and parents of European ancestry.
• Genetic Analysis: Evaluated rare de novo and other rare protein-damaging variants for enrichment and conducted gene-level analyses to identify associated genes.

Key Findings:

• Identified 12 high-confidence risk genes for OCD and 10 for CTDs.
• A total of 36 genes met the high-confidence threshold in at least one analysis, a significant increase from 4 previously identified genes.
• Approximately 7% to 8% of patients with OCD and/or CTDs carried at least one risk-contributing de novo damaging variant.
• 83% of the identified genes showed evidence from patients with both OCD and CTDs.
• High-confidence genes showed increased postnatal expression in the cerebellum and prenatal enrichment across several brain regions.

Interpretation:

The findings indicate substantial genetic overlap between OCD and CTDs, with shared genetic and neurobiological features.

Limitations:

• Incorporated previously reported samples, not designed as an independent replication.
• Focused on rare coding variants, excluding other genetic variations like copy-number and noncoding variants.
• Genotype-phenotype analyses limited by incomplete clinical information and small subgroup sizes.
• Singleton analyses restricted to patients of European ancestry.

Conclusion:

The study expands the number of high-confidence, large-effect genes implicated in OCD and CTDs, highlighting the need for further research on the functional consequences of the mutations.

Sources:

• Nature Neuroscience