Genetic Locus Associated with the Tyrosine Phosphokinase Gene Is an OCD Biomarker

PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. PTPRD is regarded as a receptor-type PTP, since it contains an extracellular region, a single transmembrane segment, and two tandem intracytoplasmic catalytic domains.

OCD is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. Investigators at Johns Hopkins University (Baltimore, MD, USA) are participants in The OCD Collaborative Genetics Association Study (OCGAS), which monitors a large group of comprehensively assessed OCD patients with an early age of OCD onset.

For the current study the investigators conducted a genome-wide association study (GWAS), scanning the genomes of more than 1,400 people with OCD and an additional 1,000 close relatives.

A GWAS is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait. A GWAS typically focuses on associations between single-nucleotide polymorphisms (SNPs) and traits such as major diseases. These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays. If one type of the variant is more frequent in people with the disease, the SNP is said to be "associated" with the disease. The associated SNPs are then considered to mark a region of the human genome which influences the risk of disease. In contrast to methods which specifically test one or a few genetic regions, a GWAS investigates the entire genome. A GWAS identifies SNPs and other variants in DNA which are associated with a disease, but cannot on its own specify which genes cause the illness.

Results of the GWAS revealed a link to OCD on chromosome 9 near the PTPRD gene. Presynaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Members of the SLITRK family, such as SLITRK3, are integral membrane proteins with two N-terminal leucine-rich repeat domains similar to those of SLIT proteins. Most SLITRKs, including SLITRK3, also have C-terminal regions that share homology with neurotrophin receptors. SLITRKs are expressed predominantly in neural tissues and have neurite-modulating activity. Both PTPRD and SLITRK3 regulate the development of inhibitory GABAergic synapses.

"If this finding is confirmed, it could be useful," said senior author Dr. Gerald Nestadt, professor of psychiatry and behavioral sciences at Johns Hopkins University. "We might ultimately be able to identify new drugs that could help people with this often disabling disorder, one for which current medications work only 60% to 70% of the time."

"OCD research has lagged behind other psychiatric disorders in terms of genetics," said Dr. Nestadt. "We hope this interesting finding brings us closer to making better sense of it and helps us find ways to treat it."

The study was published in the May 13, 2014, online edition of the journal Molecular Psychiatry.

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