For more than two decades, researchers have been collecting DNA from families affected by obsessive-compulsive disorder (OCD) and chronic tic disorders (CTDs). When they began, the technologies needed to make sense of these samples were still developing, and it was unclear whether the effort would reveal any genes with a meaningful role in the disorders.
Now, an international collaboration has identified 36 high-confidence genes associated with OCD and CTDs, compared with just four that had previously met the same statistical threshold.
The findings, published in Nature Neuroscience, provide a more detailed view of the genetic architecture for both disorders and suggest that OCD and CTDs may share some of the same underlying neurobiology. However, researchers have yet to determine whether that overlap is driven by the cumulative effects of many genetic variants or by specific variants within a smaller group of genes.
A bigger genetic map
OCD and CTDs affect an estimated one to two percent of the population and can be highly disabling. 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.
Although classified as separate disorders, the two conditions frequently occur together. Around half of people with CTDs experience obsessive-compulsive symptoms, while 20–30 percent of people with OCD have a history of tics. Their substantial genetic overlap, alongside evidence from neuroimaging and animal studies, has pointed researchers toward shared biological mechanisms, particularly involving dysfunction in the cortico-striato-thalamo-cortical (CSTC) circuitry, a network involved in processes including movement, behavior, and inhibition.
“We have long known that chronic tic disorders, including Tourette disorder, frequently co-occur with obsessive-compulsive disorder, yet the functional basis for this overlap remained unclear,” Gary Heiman, a genetic epidemiologist at Rutgers University and senior coauthor of the study, told DDN.
Previous whole-exome sequencing studies had only identified four high-confidence genes, leaving researchers with a relatively small number of biological entry points into disorders that are genetically complex.
The new study analyzed whole-exome sequencing data from 3,964 people with OCD, CTDs, or both, including 2,418 parent-child trios. The researchers looked for an excess of rare protein-damaging mutations, including de novo mutations that arise in an individual rather than being inherited from either parent.
Their analysis identified 36 high-confidence genes associated with one or both disorders. For Heiman, the expanded genetic map offers a much clearer view of the biological processes underlying OCD and CTDs.
With only a handful of genes, we could see isolated pieces of the puzzle; with 36 genes, we can begin to identify the broader cellular pathways and brain networks disrupted in both conditions.
—Gary Heiman, Rutgers University
“An analogy is increasing the magnification on a microscope,” Heiman said. “With only a handful of genes, we could see isolated pieces of the puzzle; with 36 genes, we can begin to identify the broader cellular pathways and brain networks disrupted in both conditions.”
Overall, the study found that de novo and rare pathogenic mutations were present in approximately three to eight percent of affected individuals, with the newly identified high-confidence genes carrying substantial effects. The researchers found that, on average, the high-confidence genes they studied increase the likelihood of developing OCD or CTDs by 57 times compared to people without these genetic risks. For some specific genes, the risk is even higher, increasing the chances of developing these disorders by as much as 210-fold.
The expanded gene catalog provides both a foundation for better disease models and the ability to investigate the role of individual and groups of genes. “For example, our group previously used CRISPR/Cas9 gene editing to introduce mutations in one of the risk genes in mice, resulting in behaviors resembling symptoms in humans with these disorders,” Jay Tischfield, a geneticist at Rutgers University and senior coauthor of the study, told DDN. “These animal models can help researchers investigate disease mechanisms and provide pharmaceutical companies with tools to test potential therapies.”
The disorders share more than symptoms
The larger set of genes allowed the researchers to ask whether the newly identified genes converged on common biological processes. They found that many of these genes exhibited greater connectivity with one another than would be expected by chance, suggesting that the genes may participate in interacting biological networks rather than acting independently.
This network-level view could be important for drug discovery. If several risk genes influence the same cellular pathway or biological process, researchers may not necessarily need to develop a therapy against each individual gene. Instead, understanding the shared pathways could reveal broader mechanisms that can be targeted therapeutically.
“These genes don’t act individually,” said Tischfield in the press release. “They act in networks. And now you can target whole networks, which will make it easier to design new therapies.”
The genetic picture also extended beyond OCD and CTDs. Several of the identified genes overlapped with genes previously implicated in autism spectrum disorder, developmental delay and intellectual disability, and schizophrenia. “This suggests that these conditions arise from a combination of shared neurodevelopmental mechanisms and disorder-specific biological processes directed by genes and their variations,” Heiman noted.
This overlap could give researchers another way to understand what these disorders have in common — and, importantly, what sets them apart. Comparing shared and disorder-specific genes may help researchers trace how disruptions in the same biological systems can produce different clinical outcomes.
Twenty years in the making
This work was built on decades of participation from families who donated DNA samples for research. Many of those samples were collected long before the sequencing technologies used in the current study were available.
“None of this would have been possible without the extraordinary commitment of individuals with CTDs and OCD and their families. Their willingness to participate illustrates the transformative power of patient advocacy and engagement in scientific research,” said Heiman.
However, there is still a considerable distance between identifying a risk gene and developing a medicine. Researchers need to determine what each gene does in relevant brain cells, understand how mutations disrupt those functions, and establish whether correcting or modifying those pathways can alter disease-related biology.
The researchers pointed to several possible next steps, including creating genetic models in animals, examining protein-protein interactions, and mapping how the risk genes converge across different biological processes and developmental stages.
