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OCD Risk Gene Candidates Unearthed in Sequencing Study

NEW YORK (GenomeWeb) – Variants falling in genes related to synapse functions in the brain appear to be over-represented in individuals with obsessive compulsive disorder (OCD), new research suggests.

Researchers from the Broad Institute and elsewhere narrowed in on more than 600 genes with suspected ties to OCD, or potentially related conditions such as autism spectrum disorder, in prior studies of human cases, canine compulsive disorder, and other animal models of the psychiatric condition. They then sequenced the gene set in individuals with and without OCD, focusing not only on coding sequences but also variants with potential regulatory effects.

The team's search, described in Nature Communications today, led to coding and regulatory variants that were over-represented in the discovery cases and in OCD-affected individuals from a validation cohort — a collection peppered in and around four synaptic, post-synaptic, and vesicular genes.

"Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited," Broad researchers and corresponding authors Kerstin Lindblad-Toh and Elinor Karlsson, and their colleagues wrote.

Combing through the available data for humans, dogs, mice, and other animals, the team settled on 608 candidate OCD genes and evolutionarily conserved elements with potential regulatory roles. It then used hybrid capture arrays and pooled sequencing on the Illumina GAII or HiSeq 2000 to profile 13.2 million bases of coding and regulatory sequence in 592 OCD cases and 560 controls.

The researchers annotated and prioritized tens of thousands of high-confidence SNPs in the OCD-affected and -unaffected individuals by folding in conservation, coding, and chromatin cues. The strategy "combines prior findings, targeted sequencing, and a new analytic method to efficiently identify genes and individual variants associated with complex disease risk," they explained.

Using an analytical approach that focused in on genes that were inordinately affected by such variants in the OCD cases, the team identified five suspicious genes. It subsequently did Sequenom MassARRAY iPLEX-based genotyping at dozens of variants in and around the five genes in another 727 individuals with OCD and 1,105 without.

Following these steps, the researchers were left with significant associations for coding variants in the NRXN1 and HTR2A genes, implicated in post-synaptic function, and regulatory variants in the synapse maintenance gene CTTNBP2 and the vesicle trafficking gene REEP3. All four genes are expressed in a brain region that had been linked to OCD in the past, they noted.

Through a series of cell line experiments and validation analyses using data from the Exome Aggregation Consortium (ExAC), the team validated variants in the genes and began untangling some of their functional effects. In particular, the analysis pointed to OCD-related alterations that may affect everything from synaptic cell adhesion to serotonin transport.

"In a modest-size cohort of OCD cases and controls we find associations driven by both coding and regulatory variants," the authors noted, "highlighting new potential therapeutic targets."