Researchers headed by a team at Columbia University Vagelos College of Physicians and Surgeons have linked distinct patterns of genetic mutations with obsessive-compulsive disorder (OCD) in humans. Reporting in Nature Neuroscience on their analysis of exome sequencing data from more than 1,000 individuals with OCD, the scientists say their findings “… support a contribution of rare damaging coding variation to OCD risk.” They suggest the work confirms the validity of targeting specific genes as a potential treatment approach for OCD, and also points to new avenues of study for the commonly debilitating condition.
Senior study author David Goldstein, PhD, director of the Institute for Genomic Medicine at Columbia, and colleagues reported on their study in a paper titled, “Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants.” The multi-institution collaboration also included scientists from the University of North Carolina at Chapel Hill, the David Geffen School of Medicine in Los Angeles, Harvard Medical School, and SUNY Downstate Medical Center in Brooklyn.
OCD is a neuropsychiatric condition characterized by persistent, intrusive thoughts (obsessions) and repetitive, intentional behaviors (compulsions), the authors explained. The condition, which affects 1–2% of the population, commonly runs in families, and genes are known to play a large role in determining who develops the disease. “ … Evidence from family-based studies supports a genetic contribution to the disorder,” the team wrote. But while strongly acting mutations have been hypothesized to exist in OCD, statistically reliable evidence has been difficult to obtain.
Goldstein stated, “Many neurological diseases are influenced by strongly acting mutations which can cause disease by themselves. These mutations are individually very rare but important to find because they can provide a starting point for the development of therapeutics that target precise underlying causes of disease.”
Most previous studies on the genetics of OCD have used a “candidate gene” approach, in which researchers focus on plausible genes that might be involved in pathogenesis and look for genetic signatures of risk. Although that approach has had some successes, it can lead to challenges in statistical interpretation and can miss unexpected genes. As a result, both funding agencies and the pharmaceutical industry increasingly focus on genome-wide analyses that can securely implicate genes in disease risk.
But as the researchers noted, “Genome-wide association studies of common single-nucleotide polymorphisms (SNPs) have not found variants that were associated with OCD at the genome-wide level of statistical significance, likely owing to insufficient sample size.” Goldstein further suggested, “The solution to the problem is to study all the genes in the genome at the same time and ask whether any of them have significant evidence of influencing risk. That had not been done yet at scale in OCD.”
In collaboration with Gerald Nestadt, MBBCh, a psychiatrist at Johns Hopkins University with access to a cohort of OCD patients, Goldstein’s team combined high-throughput sequencing and computational biology techniques to identify relevant genes anywhere in the genome. The investigators looked at genes that encode protein using whole exome sequencing in 1,313 OCD patients, and compared them to similarly large control groups.
The analysis identified a strong correlation between OCD and rare mutations, particularly in a gene called SLITRK5 that had been previously linked to OCD in candidate-gene studies. “SLITRK5 is a member of the SLITRK gene family, which influences excitatory and inhibitory synapse formation,” the authors wrote. Interestingly, they continued, “Slitrk5-knockout mice have been described as having increased ‘OCD-like’ behaviors, including elevated anxiety and excessive grooming … In human samples, a burden of SLITRK5 coding variants that influence synapse formation in vitro has previously been described in OCD cases relative to controls.” The study also identified a specific pattern of variation in other genes. “Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant.” As Goldstein further stated, “When you look at genes that do not tolerate variation in the human population, those are the genes most likely to cause disease, and with OCD, we see an overall increased burden of damaging mutations in those genes compared to controls. That’s telling us that there are more OCD genes to be found and where to find them.”
The authors concluded, “This study is, to our knowledge, the most comprehensive cataloguing of contributions to OCD risk from rare damaging coding SNVs [single nucleotide variants] and indels thus far. Its findings suggest that, like the genetic architecture of other neuropsychiatric disorders, OCD involves contributions to overall risk from these variants.”
Goldstein expects that the new data on SLITRK5 will encourage pharmaceutical companies and translational researchers to develop drugs that target this gene. “OCD is a disabling disorder that is twice as common as schizophrenia,” said H. Blair Simpson, MD, PhD, professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons and director of the Center for OCD & Related Disorders at New York State Psychiatric Institute, who was not involved with the new study. Two available treatments, serotonin reuptake inhibiting drugs and cognitive-behavioral therapy, are highly effective, Simpson noted, but only work on about half of patients. “Thus, these genetic findings are very exciting; they indicate that the promise of precision medicine could include OCD, ultimately transforming how we diagnose and treat this disorder.”
