Beyond the MHC: A canine model of dermatomyositis shows a complex pattern of genetic risk involving novel loci.
Juvenile dermatomyositis (JDM) is a chronic inflammatory myopathy and vasculopathy driven by genetic and environmental influences. Here, we investigated the genetic underpinnings of an analogous, spontaneous disease of dogs also termed dermatomyositis (DMS). As in JDM, we observed a significant association with a haplotype of the major histocompatibility complex (MHC) (DLA-DRB1*002:01/-DQA1*009:01/-DQB1*001:01), particularly in homozygosity (P-val = 0.0001). However, the high incidence of the haplotype among healthy dogs indicated that additional genetic risk factors are likely involved in disease progression. We conducted genome-wide association studies in two modern breeds having common ancestry and detected strong associations with novel loci on canine chromosomes 10 (P-val = 2.3X10-12) and 31 (P-val = 3.95X10-8). Through whole genome resequencing, we identified primary candidate polymorphisms in conserved regions of PAN2 (encoding p.Arg492Cys) and MAP3K7CL (c.383_392ACTCCACAAA>GACT) on chromosomes 10 and 31, respectively. Analyses of these polymorphisms and the MHC haplotypes revealed that nine of 27 genotypic combinations confer high or moderate probability of disease and explain 93% of cases studied. The pattern of disease risk across PAN2 and MAP3K7CL genotypes provided clear evidence for a significant epistatic foundation for this disease, a risk further impacted by MHC haplotypes. We also observed a genotype-phenotype correlation wherein an earlier age of onset is correlated with an increased number of risk alleles at PAN2 and MAP3K7CL. High frequencies of multiple genetic risk factors are unique to affected breeds and likely arose coincident with artificial selection for desirable phenotypes. Described herein is the first three-locus association with a complex canine disease and two novel loci that provide targets for exploration in JDM and related immunological dysfunction.
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
Jacquelyn M
JM
Evans
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.|Genomics and Computational Laboratory, Clemson University, Clemson, South Carolina, United States of America.
Rooksana E
0000-0002-9992-5198
RE
Noorai
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
Kate L
0000-0002-7946-0522
KL
Tsai
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
Alison N
0000-0001-9908-4491
AN
Starr-Moss
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
Cody M
CM
Hill
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
Kendall J
KJ
Anderson
Department of Animal Science, University of California, Davis, California, United States of America.
Thomas R
0000-0002-3139-9849
TR
Famula
Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America.
Leigh Anne
0000-0001-6621-9660
LA
Clark
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001947:Breeding; D003882:Dermatomyositis / Q000453:epidemiology / Q000235:genetics* / Q000662:veterinary; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000453:epidemiology / Q000235:genetics*; D004285:Dogs; D005095:Exoribonucleases / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D048868:Adaptor Proteins, Signal Transducing; D015395:Histocompatibility Antigens Class I; C486300:TAB1 protein, human; C039692:histocompatibility antigen DLA; D005095:Exoribonucleases; C551828:PAN2 protein, human