Genetics Gives Insights into Precision Medicine for Mental Health 

Researchers at Columbia University Vagelos College of Physicians and Surgeons have discovered a possible breakthrough in mental health precision medicine by finding a correlation between a distinct pattern of genetic mutation, called SLITRK5, and obsessive-compulsive disorder (OCD) in humans. Their findings were published online in Nature Neuroscience.

The research confirms the validity of targeting specific genes in order to develop new and more effective OCD treatments. OCD impacts between 1 and 2 percent of the population and often runs in families. While genes contribute to the determination of who develops certain conditions, the identity of many OCD genes remains unknown.

“Many neurological diseases are influenced by strongly acting mutations which can cause disease by themselves," David Goldstein, PhD, director of the Institute for Genomic Medicine at Columbia and a senior author on the new paper said in a press release. "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."

Although it has been hypothesized that there are strong acting mutations that exist in OCD, it has been difficult to supply statistically reliable evidence.

Previous studies looking at the genetics of OCD have used a candidate-gene approach. Researchers would focus on a possible gene that could be involved in pathogenesis, then look for genetic signatures of risk.

While this approach has been somewhat successful, there have been challenges when it comes to statistical interpretation. This has led to both funding agencies and the pharmaceutical industry shifting their focus to genome-wide analyses.

“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," said Goldstein.

In collaboration with Gerald Nestadt, MBBCh, a psychiatrist at Johns Hopkins University, Goldstein and his team followed the genome-wide method when examining patients with OCD. This approach used high-throughput sequencing and computational biology techniques to identify specific genes throughout the genome.

The team used whole exome sequencing to look at genes that encoded protein in more than 1,300 OCD patients. These genes were then compared to a similarly large control group. This 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.

The analysis indicated a strong correlation between OCD and rare mutations, in particular a gene called SLITRK5. SLITRK5 has been linked to ODC in past candidate-gene studies. Considering this information, Goldstein predicts pharmaceutical companies and translational researchers will begin developing drugs to target SLITRK5.

The study also shows a certain pattern of variation in other genes.

"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 said. "That's telling us that there are more OCD genes to be found and where to find them."

OCD causes uncontrollable, reoccurring thought patterns and behaviors that hinder the lives of patients daily.

"OCD is a disabling disorder that is twice as common as schizophrenia," 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 said in a press release.

Currently, there are two available treatments for OCD. These include serotonin reuptake inhibiting drugs and genitive-behavioral therapy. While both are highly effective, they only work in about half of patients according to Simpson.

"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," Simpson said.