Chances are you know someone with obsessive-compulsive disorder (OCD). It’s estimated that more than 2 million Americans struggle with this mental health condition, characterized by unwanted recurring thoughts and/or repetitive behaviors, such as excessive hand washing or constant counting of objects. While we know that OCD tends to run in families, it’s been frustratingly difficult to identify specific genes that influence OCD risk.
Now, an international research team, partly funded by NIH, has made progress thanks to an innovative genomic approach involving dogs, mice, and people. The strategy allowed them to uncover four genes involved in OCD that turn out to play a role in synapses, where nerve impulses are transmitted between neurons in the brain. While more research is needed to confirm the findings and better understand the molecular mechanisms of OCD, these findings offer important new leads that could point the way to more effective treatments.
A major challenge in searching for genes involved in complex behavioral disorders like OCD is that the specific genetic variants underlying them tend to be both rare and subtle in their effects. One way to tackle the problem is to sequence whole genomes. Though sequencing costs have dropped significantly, working with the whole genomes of hundreds or even thousands of people with OCD can get prohibitively expensive. Exome sequencing, which focuses only on protein-coding genes in about 2 percent of the human genome, is one way to lower costs. But it will miss any changes in regulatory DNA sequences, which are known to be important in many disorders.
To get around these challenges as reported in Nature Communications, researchers including Hyun Ji Noh, Elinor Karlsson, and Kerstin Lindblad-Toh at the Broad Institute of MIT and Harvard, Cambridge, MA, developed a new strategy that capitalized on available DNA data from multiple species . In fact, Karlsson and Lindblad-Toh have been studying pet dogs for years in search of genes involved in natural compulsive behaviors that canine owners know well, such as repetitive grooming or tail chasing . The breeds include Doberman Pinscher, German Shepherd, Shetland Sheepdog, and Jack Russell terrier.
The researchers wanted to see if what they’d learned about obsessive-compulsive behaviors in dogs translated to other species. So, they combined their data with existing genetic studies of mice that compulsively groom themselves and people with OCD or autism spectrum disorder (ASD), which is also characterized by repetitive behaviors.
After reviewing the evidence, the researchers decided to focus on 608 genes, including 263 from studies of dogs and mice, 196 from studies of people with ASD, and 216 from earlier studies of people with OCD. The researchers then set out to sequence those 608 target genes in 592 people of European ancestry with OCD and 560 people without. To capture potential differences in regulatory elements in addition to the protein-coding sequences, they also sequenced non-coding DNA in and around those genes, focusing on stretches of DNA that appeared to be functionally important because they’ve changed little among species.
Ultimately, the researchers found genetic variants in or around four genes that showed up again and again in people with OCD and not in the control group. Variants in two of those genes—called NRXN1 and HTR2A—tended to show up in the protein-coding sequences themselves. Variants associated with the other two—CTTNBP2 and REEP3—tended to fall in regulatory elements that would control the way those genes are expressed.
These variants in the four genes are predicted to change the formation and/or function of synapses in the brain. They are also specifically active in a brain circuit previously linked to OCD that is critical for movement and reward systems.
While there’s plenty more to learn about how these genes may influence repetitive thoughts and behaviors, NRXN1 and CTTNBP2 are both known to play a role in holding synapses together. REEP3 is thought to be involved in synaptic plasticity, which is important for the brain to form new neural connections while learning. Interestingly, HTR2A encodes a receptor found at synapses throughout the central nervous system that binds the neurotransmitter serotonin. This discovery might help to explain why selective serotonin reuptake inhibitors (SSRIs) help some dogs and people with controlling compulsive behaviors.
But many OCD sufferers aren’t helped with the treatments that are currently available. The hope is this new evidence will help point the way to a better understanding of the biological problems underlying OCD, as well as lead to the discovery of other important genes and environmental factors that contribute to the disorder.
The findings also come as yet another reminder that we can learn an awful lot from taking into account our close relationship with our “best friend,” the domestic dog. (And yes, cat owners, we have learned a lot from them too!) In fact, Karlsson is now enlisting dog owners and their dogs into an NIH-funded citizen science project called Darwin’s Dogs that is sure to bring even more insight into psychiatric and neurological diseases that affect both dogs and people.
 Integrating evolutionary and regulatory information with multispecies approach implicated genes and pathways in obsessive-compulsive disorder. Noh HJ, Tang R, Flannick J, O’Dushlaine C, Swofford R, Howrigan D, Genereux DP, Johnson J, van Grootheest G, Grünblatt E, Andersson E, Djurfeldt DR, Patel PD, Koltookian M, M Hultman C, Pato MT, Pato CN, Rasmussen SA, Jenike MA, Hanna GL, Stewart SE, Knowles JA, Ruhrmann S, Grabe HJ, Wagner M, Rück C, Mathews CA, Walitza, Cath DC, Feng G, Karlsson EK, Lindblad-Toh K. Nature Communications 2017 Oct 17; 8: 774.
 Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder. Tang R, Noh HJ, Wang D, Sigurdsson S, Swofford R, Perloski M, Duxbury M, Patterson EE, Albright J, Castelhano M, Auton A, Boyko AR, Feng G, Lindblad-Toh K, Karlsson EK. Genome Biol. 2014 Mar 14;15(3):R25.
Obsessive-Compulsive Disorder (National Institute of Mental Health/NIH)
Mental Disorders (Substance Abuse and Mental Health Services Administration/HHS)
Elinor Karlsson (University of Massachusetts Medical School and Broad Institute, Cambridge, MA)
Kerstin Lindblad-Toh (Broad Institute, Cambridge, MA)
Darwin’s Dogs (University of Massachusetts Medical School, Worcester)
NIH Support: National Institute of Mental Health