A large-scale genetic analysis has identified 36 genes carrying rare mutations that sharply raise the odds of developing obsessive-compulsive disorder (OCD) or chronic tic disorders (CTDs), or both, offering new clues about the biology behind these overlapping conditions. The work, published in Nature Neuroscience, centres on two researchers from the United States – Belinda Wang of the University of California, San Francisco, and Gary A. Heiman of Rutgers University – who led an international consortium to expand the search for high-impact genetic changes.
OCD is characterised by intrusive thoughts or images (obsessions) and repetitive behaviours or mental routines (compulsions), while CTDs, including Tourette syndrome, involve involuntary motor movements or vocalisations. Both conditions affect about 1 to 2 per cent of people globally and frequently co-occur. The study notes that roughly a third of OCD patients have a history of tics, and about half of those with CTDs display OCD symptoms.
Researchers say much inherited risk comes from common genetic variations with small effects. However, rare mutations with large effects can illuminate direct biological pathways from a disrupted gene to brain development. Prior to this study, four high-confidence risk genes for these conditions had been confirmed; the new research expands on that considerably.
The team, working with the Tourette International Collaborative Genetics (TIC Genetics) study and the Foundation for OCD Research (FFOR), gathered a much larger dataset by sequencing protein-coding regions of the genome in 3,964 individuals diagnosed with OCD, CTD or both. The patient sample split into two main groups: 2,418 parent-child trios, where a child is affected and both biological parents are available, and 1,546 singletons, affected individuals with no parental DNA available for comparison. For comparison, they used exome data from 1,734 control trios and 2,380 singleton controls from the Simons Simplex Collection.
The researchers focused on two damaging mutation types: likely gene-disrupting mutations and severe missense mutations, which alter an amino acid in a manner predicted to impair the protein. Across participants, they assessed whether patients carried a higher burden of these variants in genes that are tolerant to mutation in the general population.
In the trio analysis, children with OCD or CTD carried higher rates of spontaneous, damaging gene mutations and severe spontaneous missense mutations than control children. In contrast, rare inherited variants passed from parents were not more common in affected children, and there were no overall differences between males and females in mutation rates.
Among singletons, OCD patients showed a higher frequency of rare gene-disrupting mutations in highly constrained genes than controls. Based on these results, the authors estimate that roughly 7 to 8 per cent of trio patients carry a spontaneous damaging mutation contributing to their condition, while about 3 per cent of singleton OCD patients carry a risk-contributing rare gene-disrupting variant.
By combining evidence from spontaneous trio mutations and rare singleton variants, the researchers identified a set of high-confidence risk genes. Analyses of OCD alone yielded 12 high-confidence genes, CTD alone yielded 10, and a pooled analysis across all patients identified 34 high-confidence risk genes, bringing the total to 36 distinct genes across all analyses. Four of these matched genes already known from earlier exome studies, and four overlapped with genomic regions flagged in studies of common, small-effect OCD variants.
Mutations in these 36 genes were linked to substantial increases in risk. On average, carrying a damaging variant in one of the genes raised the odds of OCD or a CTD by about 57-fold, with individual genes associated with up to a 210-fold increase. Because these mutations are exceedingly rare in the general population, only a small fraction of all people with OCD or tic disorders carry a mutation in any given gene. Of the 36 genes, 30 showed statistical support from both OCD and tic disorder cases, reinforcing the shared biology of the two conditions.
“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.” They added that studying genetically related disorders together helped identify more of the implicated genes.
Thirty of the genes showed evidence from both conditions, which the authors say implies that converging biological processes underlie OCD and CTD. “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,” Wang and Heiman said.
The study’s authors compared the 36 genes with databases of neurodevelopmental and psychiatric conditions. The genes overlapped substantially with risk genes for autism spectrum disorder, developmental delay, intellectual disability and schizophrenia, but did not overlap with genes linked to congenital heart disease. When the team mapped the genes onto brain atlases across life stages, they found that, like autism risk genes, the broader set of genes with spontaneous damaging mutations was active in the developing brain before birth. The high-confidence OCD and tic disorder genes, however, also showed elevated activity after birth, particularly in the cerebellum and, more tentatively, in the striatum and thalamus.
Cellularly, the genes tended to be most active in excitatory projection neurons of the cortex, and to a lesser extent in medium spiny neurons of the striatum. These cells are central to the cortico-striato-thalamo-cortical circuit, a network linking the brain’s outer cortex with deeper regions involved in habit formation, movement control and reward processing.
A separate network analysis found that the 36 genes were more interconnected than expected by chance, with links to processes such as cell polarity, cilia and nerve-fibre growth. However, a database limited to direct protein–protein interactions did not show the same pattern, which the authors suggest may reflect gaps in that resource.
Wang and Heiman emphasised that the findings do not imply that all OCD or CTD cases arise from these mutations. “These findings do not mean that everyone with OCD or a CTD has a damaging mutation in one of these 36 genes. 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.”
The researchers also stressed that the study signals a dual trajectory for future work: expanding larger and more ancestrally diverse patient cohorts to uncover additional genetic contributors, and conducting laboratory experiments to observe how these human mutations alter brain wiring. They note that statistical models in the paper estimate roughly 550 genes contribute to OCD risk, 1,100 for CTD, and 760 when the conditions are considered together. In the meantime, the 36 high-confidence genes provide concrete targets for further study in cell cultures or animal models, with the aim of identifying new therapeutic avenues.
The study reflects sustained collaboration across the Foundation for OCD Research, Tourette International Collaborative Genetics, and numerous participating institutions, with researchers emphasising the importance of engaging with individuals and families affected by these disorders. “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,” the researchers concluded.
