DATE: October 26, 2026 at 06:00AM
SOURCE: PSYPOST.ORG
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TITLE: Scientists identify rare mutations in 36 genes that sharply raise the odds of OCD and tic disorders
URL: https://www.psypost.org/scientists-identify-rare-mutations-in-36-genes-that-sharply-raise-the-odds-of-ocd-and-tic-disorders/
A large-scale genetic analysis has identified 36 genes carrying rare mutations that substantially increase the likelihood of developing obsessive-compulsive disorder, chronic tic disorders, or both. By pinpointing specific biological pathways and brain regions where these genes are active, the research offers new insights into how these overlapping conditions develop. The study was published in Nature Neuroscience.
Obsessive-compulsive disorder, commonly known as OCD, is a psychiatric condition defined by unwanted, intrusive thoughts or mental images, called obsessions, alongside repetitive physical behaviors or mental routines, called compulsions, that a person performs to ease their distress. Chronic tic disorders (CTDs), which include Tourette syndrome, involve persistent, involuntary motor movements or vocal sounds that are often preceded by an uncomfortable physical sensation or urge.
Both conditions affect roughly 1 to 2 percent of the global population and frequently appear together in the same individuals. About half of all people with chronic tic disorders experience obsessive-compulsive symptoms, while 20 to 30 percent of people diagnosed with OCD have a history of tics.
Because both disorders tend to run in families, scientists know they have a strong genetic component. Much of the inherited risk comes from common genetic variations that each contribute a tiny amount to a person’s overall susceptibility. For instance, a 2026 study of Korean participants found that genetic risk scores built from European data on OCD, schizophrenia, and anorexia nervosa were each modestly associated with having OCD. Alongside these common, small-effect variations, a smaller fraction of cases involve rare genetic mutations that have a large impact on individual risk.
Finding these rare, high-impact mutations is helpful because they allow scientists to trace direct biological routes from a specific disrupted gene to changes in brain development. Prior to this investigation, researchers had only confirmed four high-confidence risk genes carrying rare mutations for these conditions: two for OCD and two for chronic tic disorders.
Lead author Belinda Wang, an assistant professor in the Department of Psychiatry and Behavioral Sciences at the University of California, San Francisco, who directs the Belinda Wang Lab, conducted the study alongside Gary A. Heiman, a professor in the Department of Genetics at Rutgers, the State University of New Jersey. They worked with a large international consortium of colleagues to expand this list by analyzing the protein-coding regions of the genome in a much larger group of patients, roughly doubling the sample sizes of earlier sequencing efforts.
“Many people with these disorders continue to experience debilitating symptoms despite treatment, and our limited understanding of the underlying biology makes it harder to develop more effective treatments,” Wang and Heiman told PsyPost. “By integrating data from the Tourette International Collaborative Genetics (TIC Genetics) study and the Foundation for OCD Research (FFOR) study, we identified substantially more genes contributing to the risk of both disorders than when each disorder was studied independently.”
To accomplish this, the researchers used a technique called whole-exome sequencing. While a person’s entire genome contains billions of DNA letters, only about 1 to 2 percent of that DNA actually provides the instructions for building proteins. Whole-exome sequencing physically isolates and reads just these protein-coding segments, known as the exome, where many large-effect disease mutations have been found. The team combined newly sequenced DNA samples with existing datasets to examine a total of 3,964 individuals diagnosed with OCD, chronic tic disorders, or both.
The patient sample was divided into two main groups based on family data availability. The first group consisted of 2,418 parent-child trios, which included an affected child and both of their biological parents, most of whom did not have either disorder. Studying complete trios allows scientists to spot “de novo” mutations, which are spontaneous genetic changes that appear for the first time in a child and were not inherited from either parent. The second group included 1,546 “singletons,” meaning affected individuals whose parents’ DNA was not available for comparison, all of whom had an OCD diagnosis and were of European ancestry.
For comparison, the researchers analyzed exome data from 1,734 control trios from the Simons Simplex Collection, consisting of unaffected siblings of children with autism and their parents, as well as 2,380 unaffected parents who served as singleton controls. When comparing the singleton groups, the researchers statistically controlled for biological sex and genetic ancestry to prevent population differences from skewing the results. Across all participants, the team looked specifically for two types of damaging genetic changes: likely gene-disrupting mutations, which prematurely cut short or scramble a protein’s blueprint, and severe missense mutations, which swap out a single amino acid in a way that is predicted to impair the resulting protein’s function.
The researchers first tested whether patients carried a higher overall burden of these damaging mutations than the unaffected controls, especially in genes that are known to be intolerant to mutation in the general human population. In the trio analyses, children with OCD or chronic tic disorders had higher rates of both spontaneous gene-disrupting mutations and severe spontaneous missense mutations compared to unaffected control children. By contrast, rare inherited variants passed down from parents were not more common in affected children than in controls, and the researchers found no differences between males and females in rates of spontaneous mutations.
Among the singletons, individuals with OCD also carried a higher frequency of rare gene-disrupting mutations in highly sensitive genes than the control group. Based on these comparisons, the authors estimated that roughly 7 to 8 percent of trio patients carry a spontaneous damaging mutation that contributes to their condition, while about 3 percent of singleton OCD patients carry a risk-contributing rare gene-disrupting variant.
Next, the scientists combined the evidence from both the spontaneous mutations in trios and the rare mutations in singletons to pinpoint specific culprit genes. The researchers labeled a gene high-confidence when the statistical evidence implied an estimated false discovery rate below 10 percent, meaning no more than about 1 in 10 genes on the list would be expected to be a false lead.
Analyzing the OCD cohort on its own yielded 12 high-confidence risk genes, while analyzing the chronic tic disorder cohort alone yielded 10. When the researchers pooled all the patients together into a single combined analysis, they identified 34 high-confidence risk genes, bringing the total number of distinct high-confidence genes identified across all analyses to 36. Four of these matched the genes known from earlier exome studies, and four, including one of those previously known genes, overlapped with genomic regions previously flagged in studies of common, small-effect OCD variants.
Mutations in these 36 genes were linked to large increases in risk. On average, carrying a damaging variant in one of these genes was associated with a 57-fold increase in the odds of having OCD or a chronic tic disorder, with individual genes ranging up to a 210-fold increase in odds compared to baseline expectations. Because these mutations are exceptionally rare in the general population, even a large relative increase means that only a small fraction of all people with OCD or tic disorders actually carry a mutation in any single one of these genes. Out of the 36 genes, 30 showed statistical support from both OCD and tic disorder cases, reinforcing the idea that the two conditions share biological roots.
“These are unusually strong genetic effects, giving us valuable clues about the underlying biology,” the researchers explained. “However, carrying one of these mutations does not make developing OCD or CTD inevitable.”
“Thirty of these genes had supporting evidence from both conditions, showing that studying genetically related disorders together can help us identify more of the genes involved,” Wang and Heiman added. “We are beginning to see evidence that these genes may affect some of the same biological processes. Understanding these shared processes could ultimately guide new treatments, potentially benefiting people beyond those who carry these particular genetic changes.”
The team also compared their newly identified genes against established genetic databases for other neurodevelopmental and psychiatric conditions. The 36 genes showed substantial overlap with known risk genes for autism spectrum disorder, developmental delay, intellectual disability, and schizophrenia, but no overlap with genes tied to congenital heart disease.
To see where and when these genes operate, the researchers mapped them onto existing atlases of human and animal brain tissue across different stages of life. Like autism risk genes, the broader set of genes carrying spontaneous damaging mutations was especially active in the developing brain before birth. Unlike autism genes, however, the high-confidence OCD and tic disorder genes also showed elevated activity after birth, most strongly in the cerebellum and, more tentatively, in the striatum and thalamus.
At the cellular level, the genes tended to be most specifically active in excitatory projection neurons of the cortex and, more tentatively, in medium spiny neurons of the striatum. These specific cell types form the backbone of the cortico-striato-thalamo-cortical circuit, a loop of brain regions that connects the brain’s outer layer, the cortex, to deeper structures involved in habit formation, movement control, and reward processing.
This aligns with a 2017 study covered by PsyPost, which found that eliminating specific synaptic receptors involved in the development of corticostriatal circuits caused mice to exhibit repetitive, OCD-like behaviors such as excessive grooming and continuous digging, though that earlier work relied on targeted genetic manipulations in animals rather than naturally occurring rare mutations in human patients.
A network analysis drawing on a database of known functional relationships between genes found that the 36 genes were more interconnected than expected by chance, with links to processes such as cell polarity, cilia, and the growth of nerve fibers. A separate database limited to direct physical contacts between proteins did not show the same pattern, which the authors suggest may reflect gaps in that resource.
“One striking finding was that these risk genes were more interconnected than expected,” Wang and Heiman noted. “Moreover, genes that interact with them also showed evidence of genetic risk for OCD or CTD. This pattern suggests that diverse genetic changes may converge on shared biological processes, although the specific mechanisms involved are still being elucidated.”
“We were also surprised to find that several of the risk genes encode proteins involved in the extracellular matrix, the material surrounding cells that helps organize their environment and shape brain circuitry and neuroplasticity,” the researchers said. “We are now investigating the proteins encoded by these genes to determine how their disruption may contribute to the development of OCD and CTD.”
There are a few things to keep in mind when interpreting these results. Whole-exome sequencing only examines the protein-coding portions of DNA, meaning the study did not capture mutations in the vast non-coding regions of the genome that regulate how genes are turned on and off, nor did it directly evaluate large structural deletions or duplications of DNA. The singleton analyses were also restricted to individuals of European descent to avoid statistical confounding, which limits how well those specific findings apply to other global populations.
In addition, among the parent-child families with OCD, tic status was unknown for 832, compared with just 36 confirmed to have no tics, which makes it harder to separate genes specific to one condition from shared ones. The authors also noted that incomplete clinical records prevented them from thoroughly testing whether specific mutations were tied to the exact age a patient’s symptoms began or to whether a person had both conditions.
“These findings do not mean that everyone with OCD or a CTD has a damaging mutation in one of these 36 genes,” Wang and Heiman emphasized. “Many different genetic and nongenetic factors can contribute, and much remains to be discovered. The findings also do not immediately change diagnosis or treatment, but they give us specific starting points for understanding the biology and working toward new, more effective treatments.”
Future research will need even larger and more ancestrally diverse patient cohorts to uncover the remaining genetic contributors, as statistical models in the paper estimate that roughly 550 genes contribute to risk for OCD, 1,100 for chronic tic disorders, and 760 when the conditions are combined. In the meantime, having a concrete list of 36 high-confidence genes gives neuroscientists a starting point for laboratory experiments. Researchers can now introduce these specific human mutations into cell cultures or animal models to observe how they alter brain wiring, which could help identify new biological targets for medications.
“We are moving in two directions: expanding our studies to find more large-effect risk genes, and understanding what these genes do and what goes wrong when they are disrupted,” the researchers told PsyPost. “To find more genes, we plan to recruit more individuals and families affected by OCD and CTD and sequence their DNA. In parallel, we are studying how these genes work together and how their disruption affects brain cells. Our long-term goal is to use that understanding to guide the development of new and more effective treatments.”
“This work depended on years of collaboration across the Foundation for OCD Research, Tourette International Collaborative Genetics, and many participating institutions,” Wang and Heiman concluded. “Perhaps most importantly, our conversations with individuals and families affected by these disorders continually remind us of why this work matters and of the hope that advances in genetics will lead to more effective, targeted treatments. While much work remains to be done, findings such as these bring us closer to that goal and provide a stronger foundation for understanding the biology of CTDs and OCD and, ultimately, improving care for those affected by them.”
The study, “Whole-exome sequencing in individuals with obsessive–compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes,” was authored by Belinda Wang, Matthew N. Tran, Sheng Wang, Yuting Liu, Emily Olfson, George Wang, Nawei Sun, Jeanselle Dea, Charles Ochieng’ Olwal, Lyvia Bertolace, Michael H. Bloch, Carolina Cappi, Yi-Chieh Chang, Denise Chavira, Barbara J. Coffey, Martha J. Falkenstein, Adam C. Frank, Martin E. Franklin, Stephanie Garayalde, Helena Garrido, Marco Grados, Rami Hatem, Allyna-London Howell, Starlette Khim, Jennie M. Kuckertz, Mindy M. Le, Allison Libby, Ryan J. McCarty, Mary E. McNamara, Daniel McNeil, Euripedes C. Miguel, Cara Nasello, Binh Nguyen, Tenzin Norbu, Lauren Oh, Ashley Ordway, Catherine Paciotti, Viviana A. Peskin, Christopher Pittenger, Helen Blair Simpson, Heather Simpson Martin, Max A. Tischfield, Jinchuan Xing, Jessica J. Zakrzewski, Tourette International Collaborative Genetics (TIC Genetics), Andrea Dietrich, Donald L. Gilbert, Pieter J. Hoekstra, Young Shin Kim, Samuel Kuperman, Alyssa Rosen, Samuel H. Zinner, Mehdi Bouhaddou, Robert A. King, Guy Rouleau, Kerry J. Ressler, Carol A. Mathews, Nevan J. Krogan, Nenad Sestan, Jay A. Tischfield, A. Moses Lee, Gary A. Heiman, Thomas V. Fernandez, A. Jeremy Willsey, and Matthew W. State.
URL: https://www.psypost.org/scientists-identify-rare-mutations-in-36-genes-that-sharply-raise-the-odds-of-ocd-and-tic-disorders/
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