Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.
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.
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America; Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Isabelle
I
Schrauwen
Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, Georgia, United States of America.
Renee M
RM
Barber
The Animal Neurology and Imaging Center, Algodones, New Mexico, United States of America.
Scott J
SJ
Schatzberg
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Ashley L
AL
Siniard
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Jason J
JJ
Corneveaux
Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
Brian F
BF
Porter
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
Karen M
KM
Vernau
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Rebekah I
RI
Keesler
Section of Clinical & Comparative Neuropathology, Ludwig Maximilians University Munich, Munich, Germany.
Kaspar
K
Matiasek
Department of Small Animal Medicine, University of Leipzig, Leipzig, Germany.
Thomas
T
Flegel
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
Andrew D
AD
Miller
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
Teresa
T
Southard
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, United States of America.
Christopher L
CL
Mariani
Department of Veterinary Pathobiology, Veterinary Medical Diagnostic Laboratory, University of Missouri, Columbia, Missouri, United States of America.
Gayle C
GC
Johnson
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Matthew J
MJ
Huentelman
D000818:Animals; D001947:Breeding; D033481:Chromosomes, Mammalian; D004283:Dog Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004285:Dogs; D044783:F-Box Proteins / Q000235:genetics* / Q000276:immunology; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D008297:Male; D008590:Meningoencephalitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000662:veterinary*; D020641:Polymorphism, Single Nucleotide; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000276:immunology; D012307:Risk Factors
D044783:F-Box Proteins; D000949:Histocompatibility Antigens Class II; D020395:Receptors, Interleukin-7