New discovery: Four genes connected with OCD

18 October 2017

Many different mutations in four genes important to the synapses of the brain can be associated with obsessive-compulsive disorder in humans. This is shown in a new study of more than 1,000 patients and roughly as many controls. The study has been conducted by an international group of researchers led by researchers at Uppsala University and the Broad Institute, USA.

Obsessive-compulsive disorder (OCD) is a hereditary disorder that affects roughly 80 million people worldwide, but the biology of the disease is poorly understood. The frontline therapeutics, which target serotonin signaling in the brain, only works in a narrow subset of patients. In a new effort to dig into the biology of OCD, a team led by Broad Institute researchers compared genetic information across multiple species that suffer from compulsive behavior disorders and identified four novel genes with OCD-associated variants in humans. The genes are involved in synapse maintenance and neurotransmitter signaling, suggesting potential mechanisms at work in the disorder. The research was published today in Nature Communications.

Looked at 600 genes with possible connection

The researchers – led by postdoctoral associate Hyun Ji Noh and co-senior authors Kerstin Lindblad-Toh, senior science director of Broad’s Vertebrate Genomics group and professor at Uppsala University, and Elinor Karlsson, director of the Vertebrate Genomics group and assistant professor at the University of Massachusetts Medical School – initially compiled a list of genetic associations from previous studies of human OCD and co-morbid disorders, mouse compulsive behavior OCD models, and canine compulsive disorder (CD). Canine CD, prevalent in certain dog breeds, often manifests as excessive licking, sucking or tail-chasing.

The team used this data to refine a list of more than 600 genes and 80,000 related regulatory elements that might be involved in human OCD.

“We were seeking ways to take advantage of information from other species in order to inform and focus the study in humans,” explains Kerstin Lindblad-Toh. “Each additional species that we looked at gave us more information about possible factors in the brain that contribute to OCD.”

Identified four genes connected with human OCD

The researchers designed targeted sequencing panels for these genes and examined them in two human cohorts, totalling more than 1,300 cases and 1,600 controls. Ultimately, the team identified four genes — NRXN1, HTR2A, CTTNBP2, and REEP3, all expressed in the brain — that had variants in either protein-coding or regulatory DNA significantly associated with human OCD.

NRXN1’s association was further supported using population-matched data from the Exome Aggregation Database as an additional set of controls. In follow-up experiments to investigate regulatory variants in CTTNBP2 and REEP3, the researchers introduced the regulatory DNA elements with mutations into human cell lines and observed changes in transcription factor binding, providing evidence for a mechanistic role in the cell.

Disrupt synapse development and neural pathways

Variants of the four genes are predicted to disrupt synapse development and throw neural pathways, including serotonin and glutamate signaling, out of balance in brain regions previously implicated in OCD. NRXN1, involved in synapse structure, and REEP3, which encodes a protein that shapes membranes within certain cells, have also been highlighted in studies of autism spectrum disorder. The data suggest new targets to pursue for an improved biological and therapeutic understanding of OCD.

This study was supported in part by a Broad Institute SPARC (Scientific Projects to Accelerate Research and Collaboration) grant. Additional funding was provided by the National Institute of Mental Health (1R21MH109938­01), AKC Health Foundation, Swedish Research Council, Swedish Medical Research Council, and European Research Council.

Full article: Hyun Ji Noh et al, 'Integrating evolutionary and regulatory information with multispecies approach implicates genes and pathways in obsessive-compulsive disorder', Nature Communication, DOI 10.1038/s41467-017-00831-x

Last modified: 2021-02-14