New research led by the Vagelos College of Physicians and Surgeons, Columbia University, has linked certain patterns of genetic mutation to obsessive-compulsive disorder (OCD) in humans.
The findings confirm that targeting certain genes can be a valid avenue for treatment against OCD, which affects between 1% to 2% of the population. We’ve known that there is a genetic component to this disorder, as it often runs in the family, but the causes of OCD had remained elusive so far.
Genes made me do it
“Many neurological diseases are influenced by strongly acting mutations which can cause disease by themselves,” says David Goldstein, PhD, director of the Institute for Genomic Medicine at Columbia and a senior author on the new paper.
“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.”
Previous work on this topic had used a “candidate gene” model, the authors explain, in which researchers focus on particular genes they believe might be involved in a certain pathogenesis — in this case, OCD. While there was some success, such approaches can also miss important genes or lead to errors in statistical interpretation of our data. In other words, it can miss parts of the story and shift our overall understanding of what causes a condition.
However, there has been a recent shift towards genome-wide analyses in this field, the team explains. In short, this approach looks at all genes in a genome at the same time, checking each of them for evidence that they’re increasing the risk of developing OCD.
In collaboration with researchers from the Johns Hopkins University’s psychiatry department, the team used this genome-wide approach to identify relevant genes in the genomes of a cohort of over 1,300 OCD patients. They compared their sequences to a similar group of control participants. 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 were also involved in the study.
They found a strong correlation between OCD and several rare mutations, but one in particular — of a gene called SLITRK5 — seemed to have the strongest association. This gene had also been identified in previous candidate-gene studies for OCD. However, the results of this study are much more reliable and the authors hope they will spur further research and development in drugs targeting the gene.
“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,” Goldstein says. “That’s telling us that there are more OCD genes to be found and where to find them.”
OCD is a condition that causes patients to have uncontrollable, recurring, and intrusive thought patterns and behaviors. It isn’t what we typically call OCD, such as the minor need to straighten a stack of books. In some, the compulsions are so severe that the person has an impending sense of dread until an action, whatever it may be, is completed. This can lead to a person spending twenty minutes opening and closing a door until they feel it has locked correctly — which is to say, it can heavily interfere with a patient’s daily life. OCD is also relatively common, affecting between 2-3% of US adults, which is twice as much compared to conditions such as schizophrenia.
Currently-available treatment avenues include serotonin reuptake inhibiting drugs and cognitive-behavioral therapy. Both are highly effective when they work, but around half of patients are resistant to either or both. A treatment that targets the genetic roots of OCD would thus be very welcome and useful for patients and doctors both.
The paper “. Exome sequencing in obsessive–compulsive disorder reveals a burden of rare damaging coding variants” has been published in the journal Nature Neuroscience.
