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dc.contributor.authorTang, Ruqi
dc.contributor.authorNoh, Hyun Ji
dc.contributor.authorWang, Dongqing
dc.contributor.authorSigurdsson, Snaevar
dc.contributor.authorSwofford, Ross
dc.contributor.authorPerloski, Michele
dc.contributor.authorDuxbury, Margaret
dc.contributor.authorPatterson, Edward E.
dc.contributor.authorAlbright, Julie
dc.contributor.authorCastelhano, Marta
dc.contributor.authorAuton, Adam
dc.contributor.authorBoyko, Adam R.
dc.contributor.authorFeng, Guoping
dc.contributor.authorLindblad-Toh, Kerstin
dc.contributor.authorKarlsson, Elinor K.
dc.date.accessioned2014-04-11T14:02:51Z
dc.date.available2014-04-11T14:02:51Z
dc.date.issued2014-03
dc.date.submitted2013-11
dc.identifier.issn1465-6906
dc.identifier.issn1474-7596
dc.identifier.urihttp://hdl.handle.net/1721.1/86097
dc.description.abstractBackground: 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.en_US
dc.description.sponsorshipBroad Institute of MIT and Harvard (Scientific Planning and Allocation of Resources Committee Grant)en_US
dc.description.sponsorshipNational Institute of Mental Health (U.S.) (Grant R01MH081201)en_US
dc.description.sponsorshipPoitras Foundationen_US
dc.publisherBioMed Central Ltden_US
dc.relation.isversionofhttp://dx.doi.org/10.1186/gb-2014-15-3-r25en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_US
dc.sourceBioMed Central Ltden_US
dc.titleCandidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorderen_US
dc.typeArticleen_US
dc.identifier.citationTang, Ruqi, Hyun Noh, Dongqing Wang, Snaevar Sigurdsson, Ross Swofford, Michele Perloski, Margaret Duxbury, et al. “Candidate Genes and Functional Noncoding Variants Identified in a Canine Model of Obsessive-Compulsive Disorder.” Genome Biology 15, no. 3 (2014): R25.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciencesen_US
dc.contributor.departmentMcGovern Institute for Brain Research at MITen_US
dc.contributor.mitauthorTang, Ruqien_US
dc.contributor.mitauthorWang, Dongqingen_US
dc.contributor.mitauthorFeng, Guopingen_US
dc.relation.journalGenome Biologyen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2014-04-04T07:23:36Z
dc.language.rfc3066en
dc.rights.holderRuqi Tang et al.; licensee BioMed Central Ltd.
dspace.orderedauthorsTang, Ruqi; Noh, Hyun; Wang, Dongqing; Sigurdsson, Snaevar; Swofford, Ross; Perloski, Michele; Duxbury, Margaret; Patterson, Edward E; Albright, Julie; Castelhano, Marta; Auton, Adam; Boyko, Adam R; Feng, Guoping; Lindblad-Toh, Kerstin; Karlsson, Elinor Ken_US
dc.identifier.orcidhttps://orcid.org/0000-0002-8021-277X
mit.licensePUBLISHER_CCen_US


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