Scientists identify rare mutations in 36 genes that sharply raise the odds of OCD and tic disorders

A comprehensive genetic study has uncovered 36 genes harboring rare mutations that significantly heighten the risk of developing either obsessive-compulsive disorder (OCD) or chronic tic disorders (CTDs). This research, published in Nature Neuroscience, provides valuable insights into the underlying biology of these overlapping conditions.

OCD, characterized by unwanted intrusive thoughts and repetitive compulsions, and CTDs, which include Tourette syndrome and involve involuntary tics, affect approximately 1 to 2 percent of the global population and often co-occur in individuals. About half of those with CTDs experience OCD symptoms, and 20 to 30 percent of OCD patients have a history of tics.

Family history suggests a strong genetic basis for these disorders, with common genetic variations contributing modestly to overall susceptibility. However, rare mutations with large impacts are also crucial, as they allow researchers to trace specific gene disruptions to alterations in brain development. Prior to this study, only four high-confidence risk genes carrying rare mutations for OCD and CTDs were identified.

Lead authors Belinda Wang and Gary Heiman expanded this list by analyzing protein-coding regions in a larger cohort of patients, effectively doubling the sample size compared to previous sequencing efforts. The team employed whole-exome sequencing, focusing on the 1 to 2 percent of DNA that codes for proteins, where most disease mutations are found.

By combining new samples with existing data, the researchers examined 3,964 individuals diagnosed with OCD, CTDs, or both. This group was divided into two main categories: 2,418 parent-child trios, where the affected child and both biological parents were studied, and 1,546 singletons, individuals with OCD diagnoses but without available parent information.

The researchers identified two types of damaging genetic changes: gene-disrupting mutations, which truncate or scramble a protein, and severe missense mutations, which alter a single amino acid, potentially impairing protein function. Individuals with OCD had a higher rate of these damaging mutations compared to unaffected controls, particularly in genes prone to mutation in the general population.

However, inherited variants from parents were not more common in affected children, and there were no gender differences in mutation rates. Among singletons, OCD patients carried a higher frequency of rare gene-disrupting mutations, offering new targets for understanding and treating these complex disorders.