title: Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy.
abstract: Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes.
  
  
  
  We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers.
  
  
  
  The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA. cbrinkmeyer@cvm.tamu.edu.
authors.forename: Candice
authors.identifier: 0000-0001-6423-8585
authors.initials: C
authors.lastname: Brinkmeyer-Langford
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Balog-Alvarez
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cai
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Davis
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.
authors.forename: Joe N
authors.initials: JN
authors.lastname: Kornegay
mesh_terms: D000483:Alleles; D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D056726:Genetic Association Studies; D055106:Genome-Wide Association Study; D006239:Haplotypes; D015810:Linkage Disequilibrium; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers
keywords: DMD; Duchenne muscular dystrophy; GRMD; Gene expression; Golden retriever muscular dystrophy; Linear mixed-model analysis; Modifier; Muscular dystrophy