An international team of researchers has identified 36 genes whose rare mutations significantly increase the likelihood of obsessive-compulsive disorder (OCD) and chronic tic disorders, including Tourette syndrome. The work was published in Nature Neuroscience.
OCD manifests as intrusive thoughts and repetitive actions that a person performs to reduce anxiety. Chronic tic disorders are involuntary movements or sounds, often following an unpleasant sensation. Both conditions occur in roughly 1-2 percent of people and often co-occur: about half of patients with tics have OCD symptoms, and 20-30 percent of people with OCD have experienced tics.
The study, led by Belinda Wang of the University of California, San Francisco, and Gary Heiman of Rutgers University, combined data from the TIC Genetics and FFOR projects. The scientists analyzed the protein-coding regions of the genome, that is, the exome, in 3,964 people with OCD, tic disorders or both diagnoses. Data from more than 4,000 people without these disorders were used for comparison.
First they checked whether patients carry more damaging mutations than people without the diagnoses. Children with OCD or tics more often had spontaneous mutations disrupting gene function compared with the control group. Inherited rare variants showed no such difference. Among adults with OCD, an elevated frequency of rare damaging mutations was also observed in genes sensitive to damage. An estimated 7-8 percent of children from family trios have a spontaneous mutation contributing to the disease, while among adults with OCD about 3 percent do.
The researchers then combined the data and identified genes with high statistical confidence. Analysis of OCD alone yielded 12 genes, tics alone 10, and a joint analysis of all patients identified 34 genes. Taking all analyses into account, the list includes 36 genes, of which 30 were confirmed in both OCD and tics. Carrying a damaging mutation in one of these genes was associated with an average 57-fold increase in the odds of a diagnosis, and for individual genes up to 210-fold. However, because such mutations are rare, only a small proportion of all patients carry them.
The authors emphasize that having a mutation does not make the disease inevitable: many genetic and non-genetic factors contribute, and much remains to be learned.
The researchers also examined where and when these genes are active. They are active in the developing brain before birth, and also after birth, especially in the cerebellum, and less confidently in the striatum and thalamus. At the cellular level, the genes are most active in excitatory neurons of the cortex and in spiny neurons of the striatum. These areas are part of a circuit linked to habit formation and movement control. In addition, the genes overlap with known risk genes for autism, developmental delay, intellectual disability and schizophrenia, but not with genes for congenital heart defects.
The work has limitations: exome sequencing does not cover non-coding regions of DNA or large structural rearrangements; the analysis of adults with OCD included only people of European ancestry; and the tic status of 832 children with OCD was unknown, complicating the separation of genes. The authors note that the results do not change diagnosis or treatment but provide concrete biological targets for future research. An estimated 550 genes are involved in the development of OCD, 1,100 in tic disorders, and 760 in both together.