title: Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder.
abstract: BACKGROUND
  Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier.
  
  
  RESULTS
  We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding.
  
  
  CONCLUSIONS
  The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.
authors.forename: Ruqi
authors.initials: R
authors.lastname: Tang
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Noh
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wang
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Ross
authors.initials: R
authors.lastname: Swofford
authors.forename: Michele
authors.initials: M
authors.lastname: Perloski
authors.forename: Margaret
authors.initials: M
authors.lastname: Duxbury
authors.forename: Edward E
authors.initials: EE
authors.lastname: Patterson
authors.forename: Julie
authors.initials: J
authors.lastname: Albright
authors.forename: Marta
authors.initials: M
authors.lastname: Castelhano
authors.forename: Adam
authors.initials: A
authors.lastname: Auton
authors.forename: Adam R
authors.initials: AR
authors.lastname: Boyko
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Elinor K
authors.initials: EK
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D017849:Animals, Inbred Strains; D000067696:Ataxin-1; D000067528:Ataxins; D002268:Carboxypeptidases / Q000235:genetics*; D051177:Catenins / Q000235:genetics*; D051187:Desmocollins / Q000235:genetics*; D004285:Dogs; D055106:Genome-Wide Association Study; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D009771:Obsessive-Compulsive Disorder / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D051177:Catenins; D051187:Desmocollins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase