Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy.

Candice Brinkmeyer-Langford,Joe N Kornegay,James J Cai,Brian W Davis,Cynthia Balog-Alvarez

doi:10.1186/s12864-016-2948-z

Abstract

BackgroundDuchenne 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.ResultsWe 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2948-z) contains supplementary material, which is available to authorized users.

Highlights

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys
It should be noted that the applicability of the results we describe here are limited to the Golden Retriever muscular dystrophy (GRMD) model, though the putative candidate genes we have identified provide support for future investigations toward the identification and characterization of modifier genes
While the power of this particular study is limited by the small number of subjects, our results indicate that GRMD phenotypes are, susceptible to genetic background

Summary

Introduction

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. 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 modify phenotypes in DMD and reveal novel therapies. Our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes. Duchenne muscular dystrophy (DMD) is an X-linked disease that causes progressive muscle degeneration in approximately 1 out of 5,000 boys [1]. Skeletal and cardiac muscle can both be affected, and, while the disease is lethal, clinical presentations of DMD vary from patient to patient (e.g. age at diagnosis, age at loss of ambulation, body mass index, and lifespan [2, 3]). Colonies of dogs have been invaluable for understanding human conditions and developing treatments (for example, Alport syndrome [13]; vaccine response [14]); careful record-keeping and cooperation by dog owners, veterinarians and researchers can benefit disease research [15]

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