Hannes Lohi1,2,3, Antti Iivanainen4, Lea Mikkola1,2,3, Kaisa Kyöstilä1,2,3, Jonas Donner5, Anu K Lappalainen6, Marjo K Hytönen1,2,3. 1. Department of Veterinary Biosciences, University of Helsinki, P.O. BOX 66 (Agnes Sjöbergin katu 2), 00014, Helsinki, Finland. 2. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. 3. Folkhälsan Research Centre, Helsinki, Finland. 4. Department of Veterinary Biosciences, University of Helsinki, P.O. BOX 66 (Agnes Sjöbergin katu 2), 00014, Helsinki, Finland. antti.iivanainen@helsinki.fi. 5. Wisdom Health, Helsinki, Finland. 6. Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
Abstract
BACKGROUND: Canine hip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants. RESULTS: We execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Fédération Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation. CONCLUSIONS: Our study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis.
BACKGROUND:Caninehip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants. RESULTS: We execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Fédération Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation. CONCLUSIONS: Our study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis.
Entities:
Keywords:
Canine; Dog; GWAS; Hip dysplasia; Neddylation; Validations study
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