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Publications

Journal Article Ppublish

PubMed: 42717174 DOI: 10.1002/age.70206

A Large-Scale Cross-Population Evaluation of Genetic Risk Variants for Dilated Cardiomyopathy in Dobermanns.

Anim Genet 57(5):e70206

Authors: Alma H Hulsman, Gwen Flokstra, Christina Kijan, Marilijn van Rumpt, Johannes C M Vernooij, Thomas C Nelson, Sophie Liu, Lieke Vree, Magdalena Harakalova, Ingrid Ljungvall, Jens Haggstrom, Gerhard Wess, Hille Fieten, Marjo K Hytönen, Hannes Lohi, Frank G van Steenbeek

Affiliations

  • Expertise Centre for Veterinary Genetics, Department Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
  • Department Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
  • Embark Veterinary, Inc. Boston, Massachusetts, USA.
  • Doberman Diversity Project, Oakland, California, USA.
  • Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands.
  • Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
  • LMU Small Animal Clinic, Ludwig Maximilians University of Munich, Munich, Germany.
  • Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
  • Department of Clinical and Medical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Folkhälsan Research Center, Helsinki, Finland.

Abstract

Previous studies suggest that genetic risk factors for dilated cardiomyopathy (DCM) in Dobermann dogs may differ between populations, complicating the use of genetic tests across subpopulations. Variants in pyruvate dehydrogenase kinase 4 (PDK4) and titin (TTN) have been associated with DCM in North American Dobermanns, whereas two loci on chromosome 5 involving Protein Kinase AMP-Activated Catalytic Subunit Alpha 2 (PRKAA2) and Ring Finger Protein 207 (RNF207) have been implicated in European populations. To assess the consistency of these signals across populations of Dobermanns, we harmonized and imputed genotype data from a Discovery cohort (n = 444) and a Replication cohort (n = 1771), and supplemented these with allele frequency data from a large diversity cohort (n = 3226) for cross-platform analyses. We detected a shared association signal near RNF207 in affected dogs in both Europe and North America. In contrast, SNPs located in and near PDK4 and TTN variants showed no association with DCM in either population. These findings indicate that the RNF207 variant represents a shared genetic risk factor for DCM in Dobermanns across populations, and support the dog, particularly the Dobermann, as a relevant spontaneous model for RNF207-driven DCM. The previously reported associations between PDK4 and TTN variants and DCM were not replicated in the North American Dobermann population, nor in the European Dobermann populations. Also, these results highlight the need for population-specific validation and functional validation of identified variants where possible, before implementation of variants in genetic testing strategies.

MeSH

Cardiomyopathy, Dilated, Genetics, Risk Factors, Cardiomyopathies