From four to 36: the genetic map linking OCD and tic disorders

Four high-confidence genes offered little room to explain why obsessive-compulsive disorder and tic disorders so often occur in the same people and families. A study published September 1 in Nature Neuroscience raised that number to 36. The increase does not reveal a single “OCD gene” or “Tourette gene.” It identifies a collection of rare variants that converge on brain circuits involved in habits, movement, and impulse control.

The team led by Belinda Wang analyzed the exome—the protein-coding portion of DNA—of 3,964 people with obsessive-compulsive disorder (OCD), chronic tic disorders, or both. The dataset included 2,418 trios consisting of an affected person and both parents, plus 1,546 participants analyzed as singletons. Comparisons included 1,734 trios of neurotypical siblings and their parents, as well as 2,380 parents of European ancestry who served as controls for the singleton analysis.

Researchers searched for mutations present in the participant but absent from the parents, along with very rare variants predicted to damage proteins. They identified 12 high-confidence genes for OCD, ten for tic disorders, and 34 when both conditions were analyzed together. After accounting for overlapping lists, the total was 36 genes at a false-discovery rate below 10%. For 30 of the 36 genes, people in both diagnostic groups contributed evidence to the association.

The pathogenic variants under study were carried by approximately 3% to 8% of affected participants. Among carriers, the genes were associated with an average odds ratio of 57, a large effect in psychiatric genetics. An odds ratio compares groups; it does not make a diagnosis inevitable. Most people with OCD or a tic disorder did not carry one of these variants, and common genetic variation, environment, and development remain part of the risk.

Gene-activity analyses pointed to increased expression in the cortex before and after birth, the striatum, and the postnatal cerebellum. Four genes also overlapped regions previously tied to OCD through common-variant studies. The set overlapped genes associated with autism, schizophrenia, and developmental delay or intellectual disability, but not congenital-heart-disease genes used as a comparison. The pattern suggests shared biology without making the conditions interchangeable.

The result is a map for experiments, not a ready-made treatment. The study examined rare coding variants and small insertions or deletions, leaving out regulatory and mitochondrial variants and larger copy-number changes. Because part of the sample had appeared in earlier research, the authors did not perform a fully independent replication. The 36 genes enable more specific cellular and animal models; the next task is to determine which changes alter circuits and which mechanisms can be targeted safely.