Integrating evolutionary & regulatory information with a multispecies approach implicates genes and pathways in Obsessive-Compulsive Disorder (OCD)

Obsessive-compulsive disorder (OCD) is a highly heritable (h2 = 0.27–0.65), debilitating neuropsychiatric disorder –– characterized by intrusive thoughts and time-consuming repetitive behaviors [as discussed recently in these GEITP pages, the h2 heritability index ranges from 1.00 (a trait reflecting 100% genetics) to zero (a trait that is a 100% environmental effect)]. More than 80 million people worldwide are estimated to suffer from OCD, and most do not find relief with available therapeutics; this fact underscores the urgency to better understand the underlying biology.

Genome-wide association studies (GWAS) have implicated glutamate signaling and synaptic proteins, but specific genes and variants have not been validated. Isolating and characterizing such genes are important for understanding the biology, and perhaps developing treatments for this devastating disease. In mouse, genetically engineered lines have causally implicated the cortico-striatal neural pathways [a system of pathways in the brain, primarily consisting of modulatory neurons from the “substantia nigra” and ventral tegmental area, as well as excitatory projections from the cortex to the striatum, where these projections form synapses with excitatory and inhibitory pathways that relay back to the cortex] in humans, mice and dogs with compulsive behavior. Mice having the Sapap3 gene deleted –– exhibit self-mutilating compulsive grooming and dysfunctional cortico-striatal synaptic transmission. The resulting compulsive grooming can be ameliorated by selective serotonin re-uptake inhibitor (SSRI) drugs, now a first-line medication for OCD.

Similarly, chronic optogenetic stimulation [using light to stimulate nerve action] of the cortico-striatal pathway in normal mice leads to compulsive grooming, accompanied by sustained increases in activity of particular neurons. Thus, excessive striatal activity, likely due to diminished inhibitory drive in the microcircuitry of these specific neurons, is a key component of compulsive grooming. The brain region disrupted in this mouse model is also implicated by imaging studies in human OCD.

Pet dogs are a natural model for OCD, amenable to genome-wide mapping, due to their unique population structure. Canine compulsive disorder (canine CD) closely parallels OCD, with equivalent clinical metrics, including compulsive extensions of normal behaviors, typical onset at early social maturity, roughly a 50% rate of response to SSRIs, high heritability, and polygenic [involvement of many genes] architecture. By means of GWAS and targeted sequencing in dog breeds with exceptionally high rates of canine CD, associated genes involved in synaptic functioning with CD have included neural cadherin (CDH2), catenin-a2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP).

Human genetic studies of related disorders, such as autism spectrum disorder (ASD), suggest additional genes. Both ASD and OCD are characterized by repetitive behaviors, and high co-morbidity suggests a shared genetic basis. GWAS searching for de novo and inherited risk-variants have confidently determined associations of the ASD multifactorial trait with hundreds of genes; this set is likely to be enriched for genes involved in OCD. Authors [see attached report] sequenced coding and regulatory elements for 608 genes potentially involved in OCD in human, mouse, and dog.

Using a new method that prioritizes likely functional variants –– authors compared 592 cases to 560 controls and found four strongly associated genes, which were then validated in a larger cohort [as mentioned in previous GEITP emails, validation in a second cohort is mandatory in some journals these days before the study can be published]. These genes included NRXN1 (neurexin-1), HTR2A (5-hydroxy-tryptamine receptor-2A), CTTNBP2 (contactin-binding protein-2), and REEP3 (receptor accessory protein-3). NRXN1 achieved genome-wide significance (P = 6.4 x 10–11) when authors included 33,370 population-matched controls. These exciting findings suggest synaptic adhesion as a key component in compulsive behaviors. Furthermore, the study shows that targeted-sequencing, plus functional annotation, can identify potentially causative variants across mammalian species, even when genomic data are limited.

Nat Commun Oct 2o17; 18: 774

Studies of Dogs, Mice, and People Provide Clues to OCD

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