30 Oct Multispecies Study Identifies Critical Genes in OCD Neurobiology
MedicalResearch.com Interview with:
Hyun Ji Noh PhD
Computational Scientist, Medical and Population Genetics
Broad Institute of MIT and Harvard
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder, characterized by intrusive thoughts and repetitive behaviors. OCD is estimated to affect roughly 80 million people worldwide, but its neurobiology remains poorly understood. To understand the disorder’s underpinnings, we searched for genetic mutations that are associated with OCD.
For this, we first identified 608 genes that were most likely to be important in OCD – some that have previously been identified in OCD-like behaviors in dogs and mice, and others in human autism, which also involves repetitive behaviors. We compared these genes in 592 people with OCD and 560 people without OCD, and found that 4 of these genes were significantly different between people with and without OCD: NRXN1, HTR2A, CTTNBP2 and REEP3. All of these four genes have important functions in the brain. Specifically, we found that the variants in NRXN1 are likely to change its ability to bind other synaptic proteins. Synaptic proteins link neurons together, and are critical for transmitting signals through the brain. We also found that the variants in CTTNBP2 and REEP3 don’t actually change the proteins made by these genes, but instead probably affect gene regulation (for example, how much of the protein is made). These ‘regulatory’ variants disrupt the binding of transcription factors (proteins that regulate expression of genes in the body) near the gene.
MedicalResearch.com: What should readers take away from your report?
Response: The significance of this study is in three-fold:
(1) We used a new comparative approach that used findings from dogs, mice and humans. This approach allowed us to focus on just 608 genes that were most likely to be important in OCD, instead of testing all ~20,000 genes in the human genome. This approach meant we didn’t need to include as many people in our study, and may be of potential use for diseases and populations that are currently underserved due to the large resources required.
(2) Since we were focusing on 608 genes instead of the entire genome, we could look into not only the protein-coding regions of the genome, but also the non-coding regulatory regions, where many genetic variants linked to psychiatric diseases are expected to be. Sequencing the whole genome is prohibitively expensive, so many studies lower costs by sequencing just the part of the genome that makes proteins, and skip the regulatory regions. Two of the genes we found, CTTNBP2 and REEP3, we found only because we included the regulatory regions, and not just the protein-coding regions.
(3) Our study provides insights into the neurobiology of OCD. We identified four genes associated with OCD, all with functions in synapse in the brain. This suggests that impairment in synapse may have a role in OCD.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: As a next step, we’re going back to dogs again. We think there is still a lot more we can learn from them – we’ve only found 4 genes so far, mostly because our studies have been quite small. We’ve now launched a huge citizen science project called Darwin’s Dogs (https://darwinsdogs.org/), where we’re asking anyone who owns a dog to come and sign up, and tell us about their dog – including whether they have any compulsive behaviors. We’ve got over 14,000 dogs signed up already.
We’re also part of a brand new research consortium that is doing a much bigger study of OCD in people, called the NORDiC consortium (www.crowleylab.org/nordic/), led by Dr. Jim Crowley. Our plan is to once again combine what we learn from dogs and people, but this time on a much bigger scale – allowing us to find far more of the genes that are involved in OCD.
Disclosures: No potential conflicts of interest
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Hyun Ji Noh, Ruqi Tang, […]Kerstin Lindblad-Toh
Nature Communications8, Article number: 774(2017)
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