A genome-wide study has identified potential risk genes that are associated with obsessive-compulsive disorder (OCD), confirming the validity of using novel targeted therapies to treat the condition.
Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition. It is characterised by uncontrollable and reoccurring thoughts, called obsessions, and repetitive behaviours, referred to as compulsions. The disorder affects around 1-2% of the population, with onset typically occurring in childhood, adolescence or early adulthood. OCD is usually treated with a combination of serotonin reuptake inhibitors (SRIs) and psychotherapy, but, unfortunately, these are only effective for half of patients.
As with other complex neuropsychiatric disorders, it is thought that rare variations contribute to OCD genetic risk. However, statistically significant evidence at a genome-wide level has been difficult to obtain, mostly due to insufficient sample sizes. Single-nucleotide polymorphisms (SNPs) are variants of a single nucleotide at a specific genome position. Their contribution to the genetic risk of OCD, along with insertion-deletion mutations (indels), has been underexplored, relative to other neuropsychiatric disorders.
Genetic patterns linked to OCD
Recently, researchers at the Columbia University Irving Medical Centre studied the largest exome-sequenced dataset for OCD to-date, to analyse SNPs and indels that may be linked to the disorder. Exome sequencing is a genomic technique for reading all the protein-coding regions of the genes in a genome.
The study of over 1,300 OCD patients showed that the most significant single-gene variation was observed in SLITRK5. This gene is a member of the SLITRK gene family, which influence excitatory and inhibitory synapse formation. The balance between excitation and inhibition in synapses is crucial for shaping the structural and functional outcomes of sensory experiences. Therefore, it is unsurprising that these neurotransmitter systems are involved in many severe mental disorders. Interestingly, the knockout of the neuron-specific transmembrane protein encoded for by SLITRK5, called SLIT and NTRK-like protein-5 (Slitrk5), was previously found to lead to OCD-like behaviours in mice.
The scientists also investigated de novo mutations (DNMs), which are genetic alterations present in an individual because of a mutation in the egg or sperm cells of one parent. A gene called CHD8, a transcriptional regulator, was the only DNM found to be a probable OCD risk gene. Mutations in CHD8 have already been implicated in autism and developmental disorders.
Novel therapeutic options
Overall, this comprehensive catalogue of coding variants suggests that, like other neuropsychiatric disorders, OCD genetic risk levels involve mutations in SNPs and indels. This is a crucial step for studies into the genetics of the disorder and confirms the validity of targeting specific genes to develop novel treatments for the disorder. For example, the new insight into SLITRK5 should encourage researchers and pharmaceutical companies to develop drugs to target this gene. Furthermore, implications of CHD8 gene dysfunction will be critical to gain a deeper understanding of the roles that damaging DNMs play in OCD.
Future studies should also focus on identifying additional risk genes for OCD. David Goldstein, Director of the Institute for Genomic Medicine at Columbia, explained: “The genes that do not tolerate variation in the human population are the genes that are most likely to cause disease. In OCD, we see an overall increased burden of damaging mutations in those genes compared to controls. This tells us that there are more genes linked to the disorder to be found.”
The location of novel risk genes will involve a combination of sequencing additional OCD case samples and conducting more extensive gene-based analysis. Ultimately, the prospect of treating OCD with precision medicine is hugely exciting because it will transform the way that the disorder is diagnosed and dealt with.
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