Genetic Variants in Serotonin Signaling Cascade Linked to Obsessive Compulsive Disorder

Obsessive Compulsive Disorder is a highly debilitating neuropsychiatric disorder with no known cause or cure. The only insight into the cause of the disorder, is the fact that it is extremely inheritable. Therefore, interested researchers are turning to genetics to identify the basis of disorder as well as a novel means of intervention. In order to identify the genes responsible for OCD like behavior, researchers from the Broad Institute at MIT and Harvard have developed a new approach of candidate gene testing. First, the authors compiled a list of 608 genes which have been shown to lead to obsessive behaviors in various model organisms, autistic spectrum disorder, and family based linkage studies of OCD. Specifically, they targeted coding regions, regulatory regions, and 82,723 evolutionary constrained elements in and around the 608 identified genes. These regions were sequenced in 592 DSM-IV OCD cases and 560 ancestry matched controls to identify 41,504 high confidence SNP’s. From there, they used three annotations specific for disease associated variation, coding, evolutionary conserved, and/or DNase 1 hypersensitivity, in order to identify functional variants. The authors continued to narrow down their hunt until they were left with 4 genes which seemed to be highly linked to OCD like behavior. NRXN1 and HTR2A are important for postsynaptic protein binding and contained coding variants while , CTTNBP2, which controls synaptic maintenance, and REEP3, which is important for vesicle trafficking, contained regulatory variants. Cumulatively, these genes are highly important for serotonin and glutamate signaling, synaptic connections, and the CSTC circuit, highlighting the link between OCD and altered neurotransmitter signaling. These results are only confirmed by the notion that many OCD patients respond positively when prescribed SSRI’s. The data from this paper not only reveal a possible cause of OCD, but also some strong biomarkers to target for future interventions.

Reference

• Noh, Hyun Ji, et al. "Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder."  Nature Communications 8.1 (2017): 774.

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