Study identifies 36 risk genes for OCD and tic disorders

A Rutgers-led international collaboration has identified 36 genes that substantially raise the risk for obsessive-compulsive disorder (OCD) and chronic tic disorders – providing what two researchers said is the most detailed biological understanding of how these conditions develop – and how they might eventually be treated.

Before this study, published in Nature Neuroscience, scientists had found a few genetic clues, each linked separately to OCD or chronic tic disorders.

Gary Heiman, a professor in the Department of Genetics in the Rutgers School of Arts and Sciences and a senior coauthor of the study, said 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.”

OCD is characterized by persistent intrusive thoughts and repetitive behaviors, while chronic tic disorders, including Tourette syndrome, involve sudden, repeated movements or vocalizations that are difficult to control. Together, the conditions affect millions worldwide, often beginning in childhood, and frequently co-occur within 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, pioneer in the study of Tourette syndrome and an emeritus Distinguished Professor in the Department of Genetics at Rutgers, and senior coauthor of the study

The study analyzed DNA from nearly 4,000 people diagnosed with OCD, chronic tic disorders such as Tourette syndrome or both conditions. Researchers focused on rare mutations that disrupt genes that help build and operate the brain.

Many of the newly identified genes are shared between OCD and chronic tic disorders. The findings help explain why the conditions often occur together in the same people and families. At the biological level, the disorders appear to involve many of the same brain pathways.

“These genes don’t act individually,” said Tischfield, who, along with Heiman is also affiliated with Rutgers’ Human Genetics Institute of New Jersey. “They act in networks. And now you can target whole networks, which will make it easier to design new therapies.”

The researchers also found several of the newly identified genes were previously linked to autism and schizophrenia, reinforcing increasing evidence that multiple psychiatric conditions may stem from related disruptions in brain development and communication.

Brain cells communicate using chemical signals called neurotransmitters that carry messages from one nerve cell to another. The genes identified in the study appear to influence how those signals move through the brain’s circuitry.

By revealing the biological systems behind the disorders, the findings could help scientists design drugs that target the underlying mechanisms rather than simply managing symptoms.

The researchers said their study also provides new insight into where these processes occur in the brain. Analyses of gene activity suggest many of the risk genes are active in regions involved in movement, decision-making and habit formation, including parts of the cortex and striatum.

The work was driven by a major international collaboration that combined genetic data from more than 30 research teams across the United States, Canada, Europe, South Korea and South America. To look for clues in the DNA, scientists used whole-exome sequencing, a technique that reads the sections of our genes that instruct the body how to make proteins. Supported by 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 helped design the project, curated clinical data and oversaw genetic sequencing.

Researchers compared gene sequences from affected individuals with those of their parents and controls. In many cases, they identified new mutations that appeared in the child but not in either parent, helping pinpoint genes that likely play a role in the disorders.

“This study really moves the field forward,” said Heiman. “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 and Tischfield have collaborated on genetic studies of brain disorders since 2007.

The researchers said the study wouldn’t have been possible without the long-term commitment of families who volunteered their DNA samples, long before modern 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,” said 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.”

Many of those families were recruited through the New Jersey Center for Tourette Syndrome and Associated Disorders and other research programs throughout the world. Their contributions allowed scientists to build the large genetic datasets needed to detect rare mutations and identify the genes involved.

Other Rutgers researchers involved in the study included Jinchuan Xing, a professor with the Department of Genetics; Max Tischfield, an assistant professor with the Department of Cell Biology and Neuroscience; Joshua Thackray, clinical research data engineer with the Office of Advanced Research Computing; Cara Nasello, a research associate with the Department of Genetics and the Department of Cell Biology and Neuroscience; and Danea Glover, program coordinator in the Rutgers Human Genetics Institute of New Jersey.

Participating organizations included: the University of California, San Francisco, the University of California, Los Angeles; the University of Rochester; the University of Florida; the University of Miami Miller School of Medicine; Harvard Medical School and McLean Hospital; the University of Southern California; Johns Hopkins University; Thomas Jefferson University; Baylor College of Medicine; the University of Washington School of Medicine; Yale University, McGill University’s Montreal Neurological Institute-Hospital; and various institutions within Europe, South America, and South Korea.