A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.
Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds--the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Matteo
M
Bianchi
Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway.
Stina
S
Dahlgren
Centre for Integrated Genomic Medical Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Jonathan
J
Massey
Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Elisabeth
E
Dietschi
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Marcin
M
Kierczak
Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway.
Martine
M
Lund-Ziener
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Katarina
K
Sundberg
Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway.
Stein Istre
SI
Thoresen
Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
Olle
O
Kämpe
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Göran
G
Andersson
Centre for Integrated Genomic Medical Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
William E R
WE
Ollier
Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Åke
Å
Hedhammar
Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
Tosso
T
Leeb
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
Kerstin
K
Lindblad-Toh
Centre for Integrated Genomic Medical Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
Lorna J
LJ
Kennedy
Department of Basic Sciences and Aquatic Medicine, Norwegian University of Life Sciences, Oslo, Norway.
Frode
F
Lingaas
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Gerli
G
Rosengren Pielberg
D000818:Animals; D001947:Breeding; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D007037:Hypothyroidism / Q000662:veterinary*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide