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Genomic Risk for Severe Canine Compulsive Disorder, a Dog Model of Human OCD Nicholas H

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Genomic Risk for Severe Canine Compulsive Disorder, a Dog Model of Human OCD Nicholas H Genomic Risk for Severe Canine Compulsive Disorder, a Dog Model of Human OCD Nicholas H. Dodman1* Edward I. Ginns2 Louis Shuster3 Alice A. Moon-Fanelli1 Marzena Galdzicka2 Jiashun Zheng4 Alison L. Ruhe5 Mark W. Neff6 1Tufts Cummings School of Veterinary Medicine, 200 Westboro Road, N. Grafton, MA 01536 2University of Massachusetts Medical School, 55 N Lake Avenue, Worcester, MA 01655. 3Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 4University of California, San Francisco, 1700 4th St., San Francisco, CA 94143-2542 5ProjectDog, 636 San Pablo Avenue, Albany, CA 94706 6Van Andel Institute, 333 Bostwick Ave N.E., Grand Rapids, MI 49503 Corresponding author: Dr. Nicholas Dodman Tufts Cummings School of Veterinary Medicine 200 Westboro Road North Grafton, MA 01536 508.887.4640 [email protected] KEY WORDS: anxiety, obsessive- graphics have enriched purebred populations compulsive disorder, CDH2, CTXN3, for founder effect mutations with tractable HTR3C, HTR3D, HTR3E, SLC12A2, stress architectures, making genotypic analyses response, Teneurin-3 advantageous. Over a pet’s lifetime, own- ers observe the animal’s stress tolerance, ABBREVIATIONS: CCD, canine compulsive arousal, and anxiety, and can inform on rich disorder; CRF, corticotropin-releasing behavioral profiles for phenotypic analy- factor; HPA, hypothalamic-pituitary-adrenal ses. Here we leverage these strengths in a axis; OCD, obsessive-compulsive disorder. search for inherited fac-tors that exacerbate ABSTRACT canine compulsive disorder (CCD), the dog counterpart to human obsesssive compulsive Dogs naturally suffer the same complex disorder (OCD). Our rationale is that iden- diseases as humans, including mental ill- tifying pathways that predispose to disease ness. The dog is uniquely suited as a model severity will expand therapeutic options, organism to explore the genetics of neuro- and ultimately bring relief to those patients psychiatric disorders. Historical breed demo- suffering the most. We have performed a Intern J Appl Res Vet Med • Vol. 14, No. 1, 2016. 1 GWAS of purebred Doberman pinschers that tonin pathway are routinely used in the treat- compares severely affected cases to mod- ment of obsessive-compulsive disorder. We erately affected cases (24:70). This GWAS hypothesize that the gene on chromosome 7 identified two statistically sig-nificant risk is essential for susceptibility to compulsive loci, on CFA34 and CFA11, and a third with disorder, and that other genes, notably ones suggestive evidence on CFA16. The locus on affecting the serotonin pathway, affect its CFA34 includes a cluster of 5-HT3 recep- severity. These findings have relevance in tor genes (HTR3C, HTR3D, and HTR3E) furthering understanding the pathophysi- that implicate a serotonergic pathway that is ology of obsessive-compulsive disorder routinely targeted by anti-OCD medications. in mammalian species and point the way The locus on CFA11 is syntenic with human toward more effective treatments that target CTXN3-SLC12A2 (5q35.1), an inherited risk both glutamate and serotonin pathways. factor for schiz-ophrenia. The third locus INTRODUCTION harbors teneurin-3 (TENM3), a modulator of the hypothalamic-pituitary-adrenal (HPA) Human obsessive-compulsive disorder axis, with effects on stress tolerance and (OCD) is a mental illness characterized by stress-related behavior. We dis-cuss candi- intrusive, distressing thoughts (obsessions) date genes and putative functional variants and time-consuming, repetitive behaviors in light of pharmacological responsiveness, (compulsions). OCD is one of the most psychiatric comorbidity, and the potential prevalent neuropsychiatric disorders, af- for gene-by-environment interactions in the fecting 1-3% of the worldwide population 1. genetic etiology of OCD and CCD. The World Health Organization (WHO) lists OCD among the 20 most disabling diseases2. AUTHOR SUMMARY Current therapies are not optimally effective We previously identified a locus on canine and extend medicinal benefit to roughly half chromosome 7 that confers susceptibility of all patients3. OCD is a multifactorial dis- to obsessive-compulsive disorder in flank order with a phenotypic spectrum. Patients and blanket sucking Doberman pinscher suffering from severe OCD report a greater dogs. The chromosome 7 locus contains a loss of time to persistent compulsions, and gene involved in the normal development of experience sub-stantially greater emotional glutamate receptors, dysfunction of which distress and psychological impairment. is involved in the expression of obsessive- Severely affected patients also respond compulsive disorder. This current study is much less frequently to available therapies, directed at identifying additional genetic and with greatly reduced benefits in quality- factors determining the severity of the con- of-life outcomes3, 4. Understanding the dition in our animal model. To this end, we general etiology of OCD may lead to broad conducted testing in severely affected versus improvements in diagnosis, treatment, and mild-moderately affected dogs to explore possibly prevention. A high clinical prior- genetic differences. We found 2 distinct ity is to alle-viate disease severity, and to regions on canine chromosomes 11 and 34 bring relief to those patients who currently that appear to be genetic modifiers affect- have the greatest unmet medical needs. ing the severity of the condition. The first, Understanding the genetic basis of severe a locus on chromosome 11, contains a gene OCD holds promise for identifying novel increasing the risk of another psychi-atric pathways, thereby expanding options for condition (schizophrenia) in humans. The improved diagnosis and therapeutic inter- second, a locus on chromosome 34 harbors vention. sero-tonin receptor genes. That serotonin The apparent genetic heterogeneity of genes are involved in determining the human OCD has been a major obstacle to severity of the condition seems particularly genetic studies with human subjects. Ad- relevant because drugs targeting the sero- ditionally, imprecise diagnosis and pheno- 2 Vol. 14, No.1, 2016 • Intern J Appl Res Vet Med. typing, comorbidity and misclassification tial as a medical model for improving the with other disorders, and societal stigma and diagnosis and treatment of psychiatric disor- privacy concerns further confound human ders in human and canine patients alike. studies. Research to understand genetic risk The genetic basis of CCD is expected to factors of OCD have met with limited suc- be tractable in breed isolates. Breed predi- 5, 6. A recent large scale GWAS involv- cess lection implies an inherited predisposition, ing thousands of human cases and controls and breed differences in the specific com- failed to detect any loci significantly pulsive behaviors co-opted by CCD further associated with OCD6. To our knowledge, suggests a genetic basis. Examples of breed a replicated locus associated with human predisposition to specific compulsions in- OCD remains elusive. clude excessive grooming in certain breeds Animal models represent an important (i.e., acral lick; 12,19), repetitive tail chasing complementary strategy for gaining access in terrier breeds10, 11, 20, and light-chasing experimentally to causative mechanisms.7, behavior in herding breeds.21 Thus genetic 8 It is widely accepted that compulsion is influences on multiple aspects of CCD can biologically conserved across mammals, be mapped serially in breeds to exploit and that experimental results with naturally independent mutations in diverse popula- occurring animal models are indeed relevant tions. Results from multiple breed studies to human OCD9, 10, 11. The literature supports may recapitulate in aggregate the biological canine compulsive disorder (CCD) as a nat- complexity observed in human OCD. urally occurring counterpart of OCD. CCD Each breed is naturally suited to genetic shares phenomenological aspects with OCD, analysis. Phenotypic variation within a breed including the repetitious nature of basic be- is attributable to founder effect variants havioral patterns and the increased anxious acting in concert with a relatively constant state of patients10, 12, 13. The early adult onset (purebred) genetic background. This limits of OCD in human patients14 is also observed phenotypic noise from modifying genes, in peri-pubertal canine patients13. The neuro- and increases the relative phenotypic effect anatomical sites of OCD and CCD also ap- of a small number of segregating loci. Each pear to share overlap. Magnetic resonance causal variant is located on an ancestral imaging in dogs showed both anterior cin- haplotype that is 50- to 100-fold larger than gulate cortex and anterior insula gray matter haplotype blocks comprising the human density reductions, implying altered activ- genome. Ancestral haplotypes are readily ity15. An fMRI study in humans with OCD detectable by GWAS with SNP densities and and hoarding disorder indicated abnormal cohort sizes that are modest relative to hu- activity in these same brain regions16. Lastly, man experimental standards. human and canine patients respond similarly to therapy. As is clinical practice in human Three previous studies have addressed medicine, veterinary medicine combines the genetics of CCD.22, 23 The first study behavioral modification with anti-OCD identified a locus on chromosome 7 CFA7( ) drugs for the treatment of CCD17. These that was associated with flank and blanket include drugs developed for human patients, sucking behavior
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