title: The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds.
abstract: Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.
authors.affiliation: Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Simon K G
authors.initials: SK
authors.lastname: Forsberg
authors.affiliation: Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden; Science for Life Laboratory & Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kierczak
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ljungvall
authors.affiliation: Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Liège, Liège Belgium.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Merveille
authors.affiliation: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Unité de Cardiologie d'Alfort (UCA), Centre Hospitalier Universitaire Vétérinaire d'Alfort, Maisons-Alfort, France.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Gouni
authors.affiliation: Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Wiberg
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Lundgren Willesen
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden; Evidensia, Animal Clinic Västerås, Västerås, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Hanås
authors.affiliation: Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Liège, Liège Belgium.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Lequarré
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Mejer Sørensen
authors.affiliation: INRA, UMR955 de Génétique Fonctionnelle et Médicale, Maisons-Alfort, France; Université Paris-Est Créteil, CNM project, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Tiret
authors.affiliation: Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Liège, Liège Belgium; Laboratory of Physiology, Faculty of Medicine, Université Libre de Bruxelles, Bruxelles, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: McEntee
authors.affiliation: Department of Veterinary Biosciences, Research Program in Molecular Neurology Research Programs Unit, University of Helsinki, Helsinki, Finland; Folkhälsan Institute of Genetics, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Seppälä
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Koch
authors.affiliation: Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Liège, Liège Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Battaille
authors.affiliation: Department of Veterinary Biosciences, Research Program in Molecular Neurology Research Programs Unit, University of Helsinki, Helsinki, Finland; Folkhälsan Institute of Genetics, Helsinki, Finland.
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Merete
authors.initials: M
authors.lastname: Fredholm
authors.affiliation: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Unité de Cardiologie d'Alfort (UCA), Centre Hospitalier Universitaire Vétérinaire d'Alfort, Maisons-Alfort, France; INSERM, U955, Equipe 03, Créteil, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Chetboul
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Häggström
authors.affiliation: Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Örjan
authors.initials: Ö
authors.lastname: Carlborg
authors.affiliation: Science for Life Laboratory & Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.affiliation: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Höglund
mesh_terms: D000818:Animals; D001947:Breeding; D033481:Chromosomes, Mammalian; D003920:Diabetes Mellitus / Q000235:genetics / Q000662:veterinary*; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005260:Female; D019270:Fructosamine / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006442:Glycated Hemoglobin / Q000235:genetics; D024602:Glyceraldehyde-3-Phosphate Dehydrogenase (NADP+)(Phosphorylating) / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D010641:Phenotype; D013045:Species Specificity
chemical_list: D019270:Fructosamine; D006442:Glycated Hemoglobin; D024602:Glyceraldehyde-3-Phosphate Dehydrogenase (NADP+)(Phosphorylating)