Limits...
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.

Show MeSH

Related in: MedlinePlus

Forest plots of four SNPs in the dog leukocyte antigen II region on chromosome 12 across three toy breeds with necrotizing meningoencephalitis.(a) BICF2P22942: p = 1.57×10−7, OR = 0.18 (0.09–0.35), (b) BICF2P738783: p = 4.11×10−8, OR = 0.18 (0.10–0.34), (c) BICF2P178662: p = 1.11×10−9, OR = 9.48 (4.19–21.40), and (d) BICF2P608380: p = 8.6×10−11, OR = 11.08 (4.72–26.01). The 95% confidence interval for each study is represented by a horizontal line, and the point estimate is given by a square, the height of which is inversely proportional to the standard error of the estimate after each study. The summary OR is indicated by a diamond with horizontal limits as the confidence limits and height inversely proportional to its standard error. The meta-analyses for all these SNPs were significant and effect sizes were in the same direction.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4231098&req=5

pone-0112755-g003: Forest plots of four SNPs in the dog leukocyte antigen II region on chromosome 12 across three toy breeds with necrotizing meningoencephalitis.(a) BICF2P22942: p = 1.57×10−7, OR = 0.18 (0.09–0.35), (b) BICF2P738783: p = 4.11×10−8, OR = 0.18 (0.10–0.34), (c) BICF2P178662: p = 1.11×10−9, OR = 9.48 (4.19–21.40), and (d) BICF2P608380: p = 8.6×10−11, OR = 11.08 (4.72–26.01). The 95% confidence interval for each study is represented by a horizontal line, and the point estimate is given by a square, the height of which is inversely proportional to the standard error of the estimate after each study. The summary OR is indicated by a diamond with horizontal limits as the confidence limits and height inversely proportional to its standard error. The meta-analyses for all these SNPs were significant and effect sizes were in the same direction.

Mentions: Additionally, we hypothesized that the genetic risk loci previously identified in pug dogs on chromosome 12 and chromosome 8 [15] may contribute to disease susceptibility in the Maltese and Chihuahua breeds. In the Maltese, genotyping of 122 SNPs within the DLA II locus (chr12∶4,713,392-8,834,652) found 17 (13.9%) that were significant (p<0.05) (Figure S4 in file S1), which is higher than the expected 5%. The most significant SNP was BICF2P178662 chr12∶5,166,878 (p = 0.001) (Figure 3). In the Chihuahua, 120 SNPs were genotyped in the same region, of which 8 were significant (6.6%) (Figure S5 in file S1). The most significant SNP was BICF2P608380 chr12∶6,289,014 (p = 0.006) (Figure 3). On chromosome 8, where STYX and GNPNAT1 are located (chr8∶31,736,206-32,225,068), 13 SNPs were analyzed in Maltese dogs and 9 SNPs were analyzed in Chihuahua dogs, but none reached significance.


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)

Forest plots of four SNPs in the dog leukocyte antigen II region on chromosome 12 across three toy breeds with necrotizing meningoencephalitis.(a) BICF2P22942: p = 1.57×10−7, OR = 0.18 (0.09–0.35), (b) BICF2P738783: p = 4.11×10−8, OR = 0.18 (0.10–0.34), (c) BICF2P178662: p = 1.11×10−9, OR = 9.48 (4.19–21.40), and (d) BICF2P608380: p = 8.6×10−11, OR = 11.08 (4.72–26.01). The 95% confidence interval for each study is represented by a horizontal line, and the point estimate is given by a square, the height of which is inversely proportional to the standard error of the estimate after each study. The summary OR is indicated by a diamond with horizontal limits as the confidence limits and height inversely proportional to its standard error. The meta-analyses for all these SNPs were significant and effect sizes were in the same direction.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112755-g003: Forest plots of four SNPs in the dog leukocyte antigen II region on chromosome 12 across three toy breeds with necrotizing meningoencephalitis.(a) BICF2P22942: p = 1.57×10−7, OR = 0.18 (0.09–0.35), (b) BICF2P738783: p = 4.11×10−8, OR = 0.18 (0.10–0.34), (c) BICF2P178662: p = 1.11×10−9, OR = 9.48 (4.19–21.40), and (d) BICF2P608380: p = 8.6×10−11, OR = 11.08 (4.72–26.01). The 95% confidence interval for each study is represented by a horizontal line, and the point estimate is given by a square, the height of which is inversely proportional to the standard error of the estimate after each study. The summary OR is indicated by a diamond with horizontal limits as the confidence limits and height inversely proportional to its standard error. The meta-analyses for all these SNPs were significant and effect sizes were in the same direction.
Mentions: Additionally, we hypothesized that the genetic risk loci previously identified in pug dogs on chromosome 12 and chromosome 8 [15] may contribute to disease susceptibility in the Maltese and Chihuahua breeds. In the Maltese, genotyping of 122 SNPs within the DLA II locus (chr12∶4,713,392-8,834,652) found 17 (13.9%) that were significant (p<0.05) (Figure S4 in file S1), which is higher than the expected 5%. The most significant SNP was BICF2P178662 chr12∶5,166,878 (p = 0.001) (Figure 3). In the Chihuahua, 120 SNPs were genotyped in the same region, of which 8 were significant (6.6%) (Figure S5 in file S1). The most significant SNP was BICF2P608380 chr12∶6,289,014 (p = 0.006) (Figure 3). On chromosome 8, where STYX and GNPNAT1 are located (chr8∶31,736,206-32,225,068), 13 SNPs were analyzed in Maltese dogs and 9 SNPs were analyzed in Chihuahua dogs, but none reached significance.

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