New Understanding of Brain Circuitry Genes Opens Door for Targeted OCD Therapies

A Rutgers-led international team co-authored a study, which was published in Nature Neuroscience, revealing 36 genes that significantly increase the risk for obsessive-compulsive disorder (OCD) and chronic tic disorders. This research offers the most comprehensive biological insight into the development of these conditions and potential future treatments.

Prior to this study, researchers had uncovered only a limited number of genetic indicators, each associated distinctly with either OCD or chronic tic disorders.

The research dramatically expands the catalog of shared risk genes, reveals biological connections with autism and schizophrenia and highlights the brain circuits that govern impulse control, movement, and habit formation.

Gary Heiman, Study Senior Co-Author and Professor, Department of Genetics, Rutgers School of Arts and Sciences, Rutgers University

Obsessive-compulsive disorder (OCD) manifests as enduring intrusive thoughts and recurrent behaviors, whereas chronic tic disorders, such as Tourette syndrome, entail abrupt, repeated movements or vocalizations that are challenging to manage. These conditions affect millions worldwide, often emerging in childhood, and frequently occur together in the same individuals and families, according to the National Institutes of Health.

In the past we knew about a couple of strong genes, so there were few opportunities for the pharmaceutical industry to develop drugs. Now you’ve got over 30 targets, and that opens up new possibilities for treatment development.

Jay Tischfield, Study Senior Co-Author and Distinguished Professor, Department of Genetics, Rutgers University

The study examined DNA obtained from almost 4,000 individuals diagnosed with OCD, chronic tic disorders like Tourette syndrome, or both conditions. Scientists focused on rare mutations that disrupt genes crucial for brain development and function.

A significant number of the recently discovered genes are common to both OCD and chronic tic disorders. These discoveries help clarify why these conditions often manifest together in individuals and their families. Biologically, the disorders appear to use many of the same brain pathways.

These genes don’t act individually. They act in networks. And now you can target whole networks, which will make it easier to design new therapies.

Jay Tischfield, Study Senior Co-Author and Distinguished Professor, Department of Genetics, Rutgers University

The researchers also observed that several of the recently identified genes had prior connections to autism and schizophrenia. This strengthens the growing body of evidence suggesting that various psychiatric conditions might originate from similar disturbances in brain development and communication.

Neurons transmit information through chemical signals called neurotransmitters, which carry messages between nerve cells. The genes identified in the study appear to affect how these signals move through the brain’s circuitry.

By uncovering the biological systems underpinning these disorders, the discoveries could help scientists develop medications that address the underlying mechanisms rather than merely alleviating symptoms.

The researchers said the study also offers new insight into the brain regions where these processes occur. Gene activity analyses suggest that many risk genes are active in areas associated with movement, decision-making, and habit formation, including parts of the cortex and striatum.

This work resulted from a large international collaboration, integrating genetic data from more than 30 research groups across the United States, Canada, Europe, South Korea, and South America. To identify genetic indicators within the DNA, scientists employed whole-exome sequencing, a method that deciphers the portions of our genes providing instructions for protein synthesis.

With support from grants from the National Institutes of Health, the New Venture Fund/Foundation for OCD Research, and the New Jersey Center for Tourette Syndrome, Rutgers researchers contributed to project design, managed clinical data, and supervised genetic sequencing.

Investigators compared gene sequences from individuals impacted by the conditions with those of their parents and control subjects. Frequently, they discovered novel mutations present in the child but absent in both parents, thereby aiding in the precise identification of genes likely to contribute to the disorders.

“This study really moves the field forward. We now have a much clearer picture of what's causing these disorders and many more directions to pursue as we work toward better treatments,” Heiman added.

Heiman and Tischfield have cooperated on genetic investigations into brain disorders since 2007.

The researchers noted that the study would not have been feasible without the enduring dedication of families who willingly provided their DNA samples, well before contemporary sequencing technologies existed.

“When we began collecting these samples 20 years ago, we did not yet have the rapid and cost-effective technologies we have today,” stated Heiman, adding that the samples were stored at the Rutgers Repository. “Families volunteered because they wanted to help scientists understand these conditions. Now, with modern genome sequencing, those samples have become incredibly valuable.”

A substantial portion of those families were enlisted via the New Jersey Center for Tourette Syndrome and Associated Disorders, along with other global research initiatives. Their input enabled scientists to build the extensive genetic datasets needed to detect rare mutations and pinpoint implicated genes.