Researchers have used whole exome sequencing (WES) to identify dozens of new risk genes associated with obsessive compulsive disorder (OCD) and chronic tic disorders (CTD) that may offer insights into the causes and a path toward novel treatment targets.
Gary Heiman, PhD, a professor in the Department of Genetics in the Rutgers School of Arts and Sciences and a senior co-author of the study, said the research “dramatically expands the catalog of shared risk genes, reveals biological connections with autism and schizophrenia and highlights the brain circuits that govern impulse control, movement, and habit formation.”
Jay Tischfield, PhD, an emeritus distinguished professor in the Department of Genetics at Rutgers, and also a senior study co-author added: “In the past we knew about a couple of strong genes, so there were few opportunities for the pharmaceutical industry to develop drugs. Now you’ve got over 30 targets, and that opens up new possibilities for treatment development.”
The researchers explain in Nature Neuroscience that OCD and CTDs, including Tourette disorder, are highly heritable, frequently co-occur, and affect 1–2% of the population. OCD is characterized by persistent intrusive thoughts and repetitive behaviors, while CTDs involve sudden, repeated movements or vocalizations that are difficult to control.
Multiple studies have investigated the genetic causes of the conditions, but so far only four genes identified by WES are considered high-confidence (hc) markers for OCD (CHD8 and SCUBE1) and CTD (CELSR3 and WWC1).
In the current analysis, the researchers examined WES data for 3964 individuals with OCD, CTDs or both.
Overall, the team identified 36 hc genes associated with one or both disorders, including 12 hcOCD, 10 hcCTD genes, and 34 combined OCDCTD hc genes, suggesting substantial genetic overlap between OCD and CTD.
Indeed, 83% of the 36 genes had evidence for association derived from both OCD and CTD cases. Just one gene (CELSR3) was associated with CTD only and five genes (BRWD1, CACNA1A, CCDC168, CHD8 and JAK2) included variants only occurring in OCD cases.
“These genes don’t act individually,” said Tischfield. “They act in networks. And now you can target whole networks, which will make it easier to design new therapies.”
The researchers found that the mutations were carried by approximately 3–8% of affected individuals and were associated with 57-fold increased risks, on average.
The team also reports that many, but not all, of the hcOCD and hcCTD risk genes significantly overlapped with genes associated with autistic spectrum disorder (ASD), developmental delay and/or intellectual disability, and schizophrenia risk genes.
This pattern was repeated in transcriptomic analyses, which showed elevated risk gene expression during prenatal cortical development, like ASD, as well as uniquely in later postnatal stages, consistent with the relatively later onset of OCD and CTDs.
The researchers say their study also provides new insight into where the biological processes occur in the brain. Analyses of gene activity suggest many of the risk genes are active in regions involved in movement, decision-making and habit formation, including parts of the cortex and striatum.
“This study really moves the field forward,” said Heiman. “We now have a much clearer picture of what’s causing these disorders and many more directions to pursue as we work toward better treatments.”
