J Vet Sci.  2019 Jan;20(1):63-71. 10.4142/jvs.2019.20.1.63.

Genome-wide association study of degenerative mitral valve disease in Maltese dogs

• Lee CM
• Song DW
• Ro WB
• Kang MH
• Park HM

• KMID: 2434779
• DOI: http://doi.org/10.4142/jvs.2019.20.1.63

Abstract

Genome-wide association study (GWAS) is a powerful tool for identifying the genetic causes of various diseases. This study was conducted to identify genomic variation in Maltese dog genomes associated with degenerative mitral valve disease (DMVD) development and to evaluate the association of each biological condition with DMVD in Maltese dogs. DNA was extracted from blood samples obtained from 48 Maltese dogs (32 with DMVD and 16 controls). Genome-wide single nucleotide polymorphism (SNP) genotyping was performed. The top 30 SNPs from each association of various conditions and genetic variations were mapped to their gene locations. A total of 173,662 loci were successfully genotyped, with an overall genotype completion rate of 99.41%. Quality control analysis excluded 46,610 of these SNPs. Manhattan plots were produced using allelic tests with various candidate clinical conditions. A significant peak of association was observed between mitral valve prolapse (MVP) and SNPs on chromosome 17. The present study revealed significant SNPs in several genes associated with cardiac function, including PDZ2, Armadillo repeat protein detected in velo-cardio-facial syndrome, catenin (cadherin-associated protein) alpha 3, low-density lipoprotein receptor class A domain containing protein 4, and sterile alpha motif domain containing protein 3. To our knowledge, this is the first study of a genetic predisposition to DMVD in Maltese dogs. Although only a limited number of cases were analyzed, these data could be the basis for further research on the genetic predisposition to MVP and DMVD in Maltese dogs.

Keyword

Dogs; Genome-wide association study; Mitral valve; Mitral valve prolapse

MeSH Terms

Animals
Armadillos
Chromosomes, Human, Pair 17
DiGeorge Syndrome
DNA
Dogs*
Genetic Predisposition to Disease
Genetic Variation
Genome
Genome-Wide Association Study*
Genotype
Mitral Valve Prolapse
Mitral Valve*
Polymorphism, Single Nucleotide
Quality Control
Receptors, Lipoprotein
DNA
Receptors, Lipoprotein

Figure

• 

  Fig. 1 Multidimensional scaling plot showing the distribution of case and control dogs in the present study. Those two outliers were excluded in this study because they were less likely to be purebred.

• 

  Fig. 2 The quantile-quantile (Q-Q) plot of 172,065 single nucleotide polymorphisms from 32 cases and 16 controls. The Q-Q plot graph from the continuous variable association with λ = 0.987 demonstrating no population stratification as seen by the consistent deviation from the line (consistency in the observed p values deviating from the expected p values).

• 

  Fig. 3 Manhattan plots of the results of genome-wide association studies of each assessed condition. The conditions were degenerative mitral valve disease phenotype (A), American College of Veterinary Internal Medicine class (B), presence of mitral valve prolapse (C), leukocytosis (D), thrombocytosis (E), and vertebral heart scale group (F). The Fisher's exact test was applied to panels A, C, D and E in Fig. 3, and the linear regression test was applied to panels B and F in Fig. 3. Chromosome numbers are shown on the x-axis and results for each chromosome are shown in the diagram in black (odd-numbered chromosomes) and gray (even-numbered chromosomes). The y-axis is the −log10 of the calculated p values.

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