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Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

Schrauwen I, Barber RM, Schatzberg SJ, Siniard AL, Corneveaux JJ, Porter BF, Vernau KM, Keesler RI, Matiasek K, Flegel T, Miller AD, Southard T, Mariani CL, Johnson GC, Huentelman MJ - PLoS ONE (2014)

Bottom Line: Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively).This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds.In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II.

View Article: PubMed Central - PubMed

Affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America; Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

ABSTRACT
Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7) and 15 (chr15:53338796A>G, p = 1.5×10-7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

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Manhattan plot of genome wide association analysis in Maltese dogs with necrotizing meningoencephalitis.The raw –log10 p-values for each SNP as determined by Fisher’s exact tests are plotted (y axis) against the chromosome position (x axis). The horizontal gray line represents the threshold for significant association after Bonferroni correction. Regions that reach genome wide significance are indicated in black.
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pone-0112755-g001: Manhattan plot of genome wide association analysis in Maltese dogs with necrotizing meningoencephalitis.The raw –log10 p-values for each SNP as determined by Fisher’s exact tests are plotted (y axis) against the chromosome position (x axis). The horizontal gray line represents the threshold for significant association after Bonferroni correction. Regions that reach genome wide significance are indicated in black.

Mentions: Association testing in Maltese dogs revealed two regions that reached genome wide significance on chromosome 4 (chr4∶74,522,353T>A, p = 8.07×10−7) and chromosome 15 (chr15∶53,338,796A>G, p = 1.55×10−7) (Table 1, Figure 1, File S2), while association testing in Chihuahua dogs did not reveal any regions of genome wide significance (Figure S1 in file S1). The region identified on chromosome 4 spreads about 10 Mega-basepairs (Mb), with the region of highest significance spanning approximately 4.4 Mb between chr4∶71,506,894-75,929,427 (Figure S2 in file S1). A tBLASTn query identified 44 human proteins mapped to this region of the canine genome (Table S1 in file S1, Figure 2). The second region on chromosome 15 spreads about 1.9 Mb between chr15∶51,567,064-53,471,253 and using tBLASTn, 19 human proteins mapped to this region of the canine genome (Table S1 in file S1, Figure 2). Additionally, all genes in these regions were prioritized based on ENDEAVOUR gene prioritization with a training set of human multiple sclerosis genes [20], which resulted in prioritization of IL7R on chromosome 4 and FBXW7 on chromosome 15 (Table S1 in file S1, Figure 2).


Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

Schrauwen I, Barber RM, Schatzberg SJ, Siniard AL, Corneveaux JJ, Porter BF, Vernau KM, Keesler RI, Matiasek K, Flegel T, Miller AD, Southard T, Mariani CL, Johnson GC, Huentelman MJ - PLoS ONE (2014)

Manhattan plot of genome wide association analysis in Maltese dogs with necrotizing meningoencephalitis.The raw –log10 p-values for each SNP as determined by Fisher’s exact tests are plotted (y axis) against the chromosome position (x axis). The horizontal gray line represents the threshold for significant association after Bonferroni correction. Regions that reach genome wide significance are indicated in black.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231098&req=5

pone-0112755-g001: Manhattan plot of genome wide association analysis in Maltese dogs with necrotizing meningoencephalitis.The raw –log10 p-values for each SNP as determined by Fisher’s exact tests are plotted (y axis) against the chromosome position (x axis). The horizontal gray line represents the threshold for significant association after Bonferroni correction. Regions that reach genome wide significance are indicated in black.
Mentions: Association testing in Maltese dogs revealed two regions that reached genome wide significance on chromosome 4 (chr4∶74,522,353T>A, p = 8.07×10−7) and chromosome 15 (chr15∶53,338,796A>G, p = 1.55×10−7) (Table 1, Figure 1, File S2), while association testing in Chihuahua dogs did not reveal any regions of genome wide significance (Figure S1 in file S1). The region identified on chromosome 4 spreads about 10 Mega-basepairs (Mb), with the region of highest significance spanning approximately 4.4 Mb between chr4∶71,506,894-75,929,427 (Figure S2 in file S1). A tBLASTn query identified 44 human proteins mapped to this region of the canine genome (Table S1 in file S1, Figure 2). The second region on chromosome 15 spreads about 1.9 Mb between chr15∶51,567,064-53,471,253 and using tBLASTn, 19 human proteins mapped to this region of the canine genome (Table S1 in file S1, Figure 2). Additionally, all genes in these regions were prioritized based on ENDEAVOUR gene prioritization with a training set of human multiple sclerosis genes [20], which resulted in prioritization of IL7R on chromosome 4 and FBXW7 on chromosome 15 (Table S1 in file S1, Figure 2).

Bottom Line: Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively).This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds.In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II.

View Article: PubMed Central - PubMed

Affiliation: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America; Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

ABSTRACT
Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7) and 15 (chr15:53338796A>G, p = 1.5×10-7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

Show MeSH
Related in: MedlinePlus