ONLINE SUPPORTING MATERIAL
Nicholas H. Dodman et al.
Phenotype Description and Significance:
Spontaneously occurring animal models of OCD have been described since the early 1990s, with
acral lick in large breed dogs being the classical representation 1,2. Since that time, many other
animal compulsive disorders have been described that have compelling parallels with the human
condition, including face validity and predictive validity (including pharmacological
responsiveness) 3 - 6. The full construct of animals with spontaneously occurring compulsions as
models of human OCD, including genetic underpinnings and physiological homology, has yet to
be established. Our genome wide association study provides the first step in that direction by
identifying a highly significant association of canine compulsive disorder (CCD) in Doberman
pinschers with the CDH2 region on chromosome 7 that is the first genetic locus identified for
any animal compulsive disorder. This finding becomes even more compelling in light of recent
studies implicating cadhedrin genes in autistic spectrum disorders, which bear many similarities
to OCD 8 - 11.
Canine compulsive disorder (CCD) is diagnosed in between 2 and 5% of dogs seen by veterinary
behaviorists (1). The symptoms are often brought on by anxiety or stress that the dog cannot
control, starting as displacement behavior in response to the stress. The behavior eventually
becomes "fixed" and is displayed in absence of stressors. In Doberman pinschers, compulsive
disorders include flank sucking and blanket sucking with some affected dogs also displaying pica
and acral lick dermatitis (ALD). Flank sucking is characterized by repetitive mouthing and
sucking of the flank region, resulting in effects ranging from a rough, dampened coat to alopecia
to raw, open skin lesions. Medical issues resulting from blanket sucking are more commonly
associated with ingestion of blanket pieces. ALD is most commonly observed in Dobermans,
Retrievers, Great Danes, and German Shepherds. Trauma resulting from affected dogs licking
the lower extremities of the limbs can lead to ulceration and infection at the site. All CCDs
appear to have a strong genetic component as evidenced by breed predilection. A Doberman
pincher genealogy showing the transmission of the blanket and flank sucking within the breed is
shown in the figure S1.
Sample Collection and Processing
Blood samples, obtained with owner consent from affected and control Dobermans, were
collected in EDTA tubes and stored at 4C until DNA was manually extracted using the Puregene
DNA purification Kit (Gentra Systems) protocol. Subsequently, a genome wide association and
subsequent fine mapping was performed.
Association parameters:
The canine Affymetrix v2 arrays contain 49,663 SNPs. After removing 34,963 SNPs with minor
allele frequencies (MAFs) < 5% or genotyping rate < 95%, we measured association of the
remaining 14,700 SNPs to CCD using the software package PLINK
genome-wide significance using 10,000 random permutations.
12
, empirically assessing
Figure S1: An example pedigree of Doberman pinschers with canine compulsive disorder.
References:
1. Goldberger E, Rapoport JL. Canine acral lick dermatitis: response to the antiobsessional drug
clomipramine. Journal of the American Animal Hospital Association 1991; 27(2) 179-182.
2. Rapoport JL, Ryland DH, Kriete M. Drug treatment of canine acral lick. An animal model of
obsessive-compulsive disorder. Arch Gen Psychiatry. 1992 Jul;49(7):517-21.
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Eds Jonathon S Abramowitz, Arthur c. Houts. Springer Science. New York. 2005. Pp 53-72.
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linkage analyses. Am. J. Hum. Genet. 81, 559-575 (2007).
Postscript:
The authors wish to acknowledge the assistance of Dr. Kathryn Meurs, College of Veterinary
Medicine at Washington State University, for allowing us access to some of her Doberman
samples.