Study identifies 36 genes linked to higher risk of OCD and chronic tic disorders

OCD involves unwanted, intrusive thoughts and repeated behaviors or mental rituals. Chronic tic disorders involve movements or sounds that are hard to control. The two conditions can occur together, and this study looked for rare genetic changes that may help explain part of that overlap.

The researchers used whole-exome sequencing, a method that examines the parts of DNA that contain instructions for making proteins. They studied 3,964 people with OCD, chronic tic disorders, or both. The group included 2,418 trios, meaning an affected person and both biological parents. This family-based design can help researchers identify de novo mutations, which are genetic changes found in a child but not in either parent.

The team reported an excess of de novo and rare protein-damaging mutations in people with these conditions. Protein-damaging mutations are DNA changes predicted to disrupt how a protein works. From their analysis, the researchers identified 36 high-confidence risk genes. Their threshold for calling a gene high-confidence used a statistical measure called a false discovery rate below 0.1.

Four of the 36 genes had already been identified as high-confidence genes: CELSR3, CHD8, SCUBE1 and WWC1. Four genes also overlapped with locations previously highlighted in broader genetic studies of OCD: BRWD1, CELSR3, QRICH1 and SYNE1.

The study found that risk genes were shared across OCD, chronic tic disorders and other neurodevelopmental conditions. That does not mean these conditions are the same, or that a gene determines an individual’s diagnosis. Instead, it suggests that some conditions may involve overlapping biological processes.

The researchers also used gene-expression and network analyses. These approaches look at how genes may work together and where in the brain they are active. The analyses pointed to increased expression of risk genes in the cerebellum after birth, and in the cortex and striatum before and after birth. These are brain regions that researchers can investigate further to understand the biology involved.

This was a genetic discovery study, not a treatment trial. It did not test a medicine, therapy or prevention strategy. It also did not establish how much risk any one gene creates for an individual, and it cannot show that carrying a particular variant causes OCD or a tic disorder.

The next steps include confirming these gene findings in additional groups, studying how the identified variants affect cells and brain circuits, and determining whether the pathways they highlight can safely lead to useful treatments. For now, the work provides a larger set of genetic leads for that research.