New Study Identifies 30 Genetic Regions Linked to Obsessive-Compulsive Disorder

Scientists have uncovered the most comprehensive genetic map of obsessive-compulsive disorder (OCD) to date, identifying 30 regions on the human genome associated with this challenging mental health condition.

The research, published in Nature Genetics, analyzed data from over 50,000 people with OCD and 2 million controls, pinpointing approximately 250 genes that likely contribute to the disorder. This landmark discovery provides unprecedented insights into the biological underpinnings of OCD and its relationship with other psychiatric conditions.

The international study marks a transition from the early phase of genetic discovery in OCD research to a new era of understanding. The findings reveal that OCD is highly polygenic, with approximately 11,500 genetic variants contributing to 90% of its heritability—more than conditions like schizophrenia but less than major depression. The research also highlights specific brain regions and cell types where these genes are most active, offering potential new targets for treatment.

Brain Circuits and Cell Types Behind OCD

For decades, scientists have sought to understand the biological basis of OCD, which affects approximately 1-3% of the population worldwide. This condition, characterized by intrusive thoughts and repetitive behaviors, carries profound personal and societal costs, including increased risk of suicide and overall mortality.

The new research identifies specific types of brain cells where OCD-associated genes are most active. The strongest signals were found in excitatory neurons in the hippocampus and cerebral cortex, along with dopamine receptor-containing medium spiny neurons in the striatum.

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These findings align with traditional neural circuit models of OCD, which focus on communication pathways between the frontal cortex and striatum. They also validate numerous brain imaging studies that have consistently implicated these regions in OCD.

Key Genes and Their Functions

Among the 250 genes associated with OCD, researchers identified 25 as the most likely causal candidates. Several stand out as particularly important:

• CTNND1, which encodes a cell adhesion molecule called p120 catenin, with evidence showing altered expression in the dorsolateral prefrontal cortex
• WDR6 and DALRD3, which showed the strongest evidence from gene-based analyses and have previously been linked to other psychiatric disorders
• CELSR3, which encodes a protein highly expressed in the developing basal ganglia and has been linked to Tourette syndrome, a condition that frequently co-occurs with OCD
• Multiple genes in the Major Histocompatibility Complex (MHC) region, an area with known connections to the immune system and several psychiatric disorders

Interestingly, DLGAP1, a gene previously implicated in OCD, was not confirmed in this larger study, highlighting how expanded research can refine our understanding of complex conditions.

Genetic Connections to Other Conditions

The study revealed substantial genetic overlap between OCD and other psychiatric disorders. The strongest genetic correlations were observed with anxiety disorders, depression, anorexia nervosa, and Tourette syndrome—all conditions that frequently co-occur with OCD.

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What surprised researchers was the discovery of negative genetic correlations between OCD and inflammatory bowel diseases like Crohn’s disease and ulcerative colitis. Despite previous studies suggesting links between OCD and autoimmunity, this finding indicates a more complex relationship where some genetic factors that increase OCD risk may actually be protective against certain autoimmune conditions.

Implications for Understanding and Treatment

How might these discoveries change our approach to OCD? The identification of specific genes and brain circuits provides potential targets for new treatments. It also helps explain why current medications, which often target serotonin and dopamine systems, can be effective for some patients.

“I hope it will reduce the stigma around OCD, showing that this is at least partly in your biology. We want to let people know there is something we can do to help and we are on our way to developing better targeted therapies for those who are suffering,” said Professor Eske Derks, senior group leader of the Translational Neurogenomics Laboratory at QIMR Berghofer.

The genetic patterns observed also help explain the significant clinical heterogeneity in OCD. Different genetic profiles may contribute to different OCD subtypes, from contamination fears and cleaning rituals to checking behaviors and intrusive thoughts.

Future Directions for Research

While this study represents a major advance, the researchers note several important limitations and future directions. The current work focused primarily on individuals of European ancestry, and more diverse populations must be included in follow-up studies. Additionally, the analysis could not confidently assess rare genetic variants or X chromosome associations, areas that will require further investigation.

The finding that common genetic variants explain only a modest amount of the total variation in OCD suggests that other types of genetic variation, including rare variants, also play important roles. Recent whole-exome sequencing studies indicate that up to 22% of OCD cases may be influenced by rare de novo coding variants, particularly in genes that are intolerant to loss of function.

As Dr. Emily O’Leary, a clinical psychologist and OCD specialist, observed: “What happens in clinical practice is that clients will come to us, typically 10 to 14 years after diagnosis and by this time they are really unwell. What this research shows us is that we can be more proactive and actually start looking at who is more likely to develop the disorder.”

The research team is now working to translate these genetic discoveries into clinical applications, including identifying existing medications that might be repurposed for OCD treatment. With approximately 500,000 Australians affected by OCD and millions more worldwide, these advances offer new hope for earlier diagnosis, better treatments, and reduced stigma for a condition that has traditionally been under-researched and misunderstood.