Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder

Ruqi Tang, Hyun J. Noh, Dongqing Wang, Snaevar Sigurdsson, Ross Swofford, Michele Perloski, Margaret Duxbury, Edward E. Patterson, Julie Albright, Marta Castelhano, Adam Auton, Adam R. Boyko, Guoping Feng, Kerstin Lindblad-Toh, Elinor K. Karlsson

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberR25
JournalGenome Biology
Volume15
Issue number3
DOIs
StatePublished - Mar 14 2014

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obsessive-compulsive disorder
Obsessive-Compulsive Disorder
Canidae
Dogs
gene
dogs
Genes
genes
breeds
cadherins
Cadherins
dog breeds
Psychiatry
Doberman Pinscher
carboxypeptidases
Catenins
behavior disorders
human cell lines
etiology
dog

ASJC Scopus subject areas

  • Genetics
  • Cell Biology
  • Ecology, Evolution, Behavior and Systematics
  • Medicine(all)

Cite this

Tang, R., Noh, H. J., Wang, D., Sigurdsson, S., Swofford, R., Perloski, M., ... Karlsson, E. K. (2014). Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder. Genome Biology, 15(3), [R25]. https://doi.org/10.1186/gb-2014-15-3-r25

Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder. / Tang, Ruqi; Noh, Hyun J.; 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 K.

In: Genome Biology, Vol. 15, No. 3, R25, 14.03.2014.

Research output: Contribution to journalArticle

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 2014, 'Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder', Genome Biology, vol. 15, no. 3, R25. https://doi.org/10.1186/gb-2014-15-3-r25
Tang, Ruqi ; Noh, Hyun J. ; 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 K. / Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder. In: Genome Biology. 2014 ; Vol. 15, No. 3.
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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.",
author = "Ruqi Tang and Noh, {Hyun J.} and Dongqing Wang and Snaevar Sigurdsson and Ross Swofford and Michele Perloski and Margaret Duxbury and Patterson, {Edward E.} and Julie Albright and Marta Castelhano and Adam Auton and Boyko, {Adam R.} and Guoping Feng and Kerstin Lindblad-Toh and Karlsson, {Elinor K.}",
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AU - Swofford, Ross

AU - Perloski, Michele

AU - Duxbury, Margaret

AU - Patterson, Edward E.

AU - Albright, Julie

AU - Castelhano, Marta

AU - Auton, Adam

AU - Boyko, Adam R.

AU - Feng, Guoping

AU - Lindblad-Toh, Kerstin

AU - Karlsson, Elinor K.

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N2 - 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.

AB - 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.

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