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Mapping the genes for complex canine autoimmune diseases

Massey, Jonathan Peter

[Thesis]. Manchester, UK: The University of Manchester; 2012.

Access to files

Abstract

The aetiology of autoimmune disease is a complex interplay between genetics, environment and immunological regulation. Our understanding of the genetic aspects of autoimmunity has increased with recent findings from Genome Wide Association Studies (GWAS). There is now a movement towards meta-analyses of GWA studies in order to increase the number of genetic loci detected. There are also efforts to detect common genetic risk factors amongst groups of diseases that potentially share common aetiopathogenic pathways. Animal models have formed the basis of many genetic discoveries and the domestic dog presents a spontaneous model for many diseases, including autoimmunity. Through man’s efforts to create specific breeds, the dog has acquired a genomic architecture consisting of long haplotype blocks and extensive linkage disequilibrium. This means that a GWAS can be conducted in dog breeds with fewer samples and fewer markers than an equivalent study in humans, reducing costs, cohort collection times, and data handling/storage considerations. Successful canine GWA studies are now starting to be published. Building upon this success, the findings from GWA studies in three canine autoimmune diseases (across six different breeds), with equivalent human pathologies, are presented. Dogs with diabetes mellitus (similar to latent autoimmune diabetes of adulthood in man), lymphocytic thyroiditis (similar to Hashimoto’s thyroiditis), and anal furunculosis (similar to perianal Crohn’s disease) were compared to control dogs to identify genetic susceptibility loci underlying disease. Follow-up genotyping of the top hits from the GWAS analyses were conducted to replicate findings and to better characterise the diseases across a number of dog breeds. Typing of MHC class II genes, important in the immune response, was also undertaken in canine diabetes mellitus and canine lymphocytic thyroiditis. In anal furunculosis, high-throughput, next-generation sequencing was utilised to identify novel mutations and fine-map associations at discovered loci. Several genes were identified in all of these canine autoimmune diseases, many with good candidate function. Some of these genes indicated common genetic susceptibility loci and pathways between canine autoimmune diseases. Breed-specific genetic effects underlying canine diabetes mellitus and canine lymphocytic thyroiditis were identified, which has implications for disease diagnosis and clinical management. Novel loci for investigation in the corresponding human disease studies have been identified and future work will begin to genetically link the conditions in dog and man.

Additional content not available electronically

CD-ROM containing: SNPs discovered by next-generation sequencing in anal furunculosis, GWAS results files, meta-analysis results files, Sequenom primer sequences

Bibliographic metadata

Type of resource:
Content type:
Form of thesis:
Type of submission:
Degree type:
Doctor of Philosophy
Degree programme:
PhD Medicine (Population Health)
Publication date:
Location:
Manchester, UK
Total pages:
277
Abstract:
The aetiology of autoimmune disease is a complex interplay between genetics, environment and immunological regulation. Our understanding of the genetic aspects of autoimmunity has increased with recent findings from Genome Wide Association Studies (GWAS). There is now a movement towards meta-analyses of GWA studies in order to increase the number of genetic loci detected. There are also efforts to detect common genetic risk factors amongst groups of diseases that potentially share common aetiopathogenic pathways. Animal models have formed the basis of many genetic discoveries and the domestic dog presents a spontaneous model for many diseases, including autoimmunity. Through man’s efforts to create specific breeds, the dog has acquired a genomic architecture consisting of long haplotype blocks and extensive linkage disequilibrium. This means that a GWAS can be conducted in dog breeds with fewer samples and fewer markers than an equivalent study in humans, reducing costs, cohort collection times, and data handling/storage considerations. Successful canine GWA studies are now starting to be published. Building upon this success, the findings from GWA studies in three canine autoimmune diseases (across six different breeds), with equivalent human pathologies, are presented. Dogs with diabetes mellitus (similar to latent autoimmune diabetes of adulthood in man), lymphocytic thyroiditis (similar to Hashimoto’s thyroiditis), and anal furunculosis (similar to perianal Crohn’s disease) were compared to control dogs to identify genetic susceptibility loci underlying disease. Follow-up genotyping of the top hits from the GWAS analyses were conducted to replicate findings and to better characterise the diseases across a number of dog breeds. Typing of MHC class II genes, important in the immune response, was also undertaken in canine diabetes mellitus and canine lymphocytic thyroiditis. In anal furunculosis, high-throughput, next-generation sequencing was utilised to identify novel mutations and fine-map associations at discovered loci. Several genes were identified in all of these canine autoimmune diseases, many with good candidate function. Some of these genes indicated common genetic susceptibility loci and pathways between canine autoimmune diseases. Breed-specific genetic effects underlying canine diabetes mellitus and canine lymphocytic thyroiditis were identified, which has implications for disease diagnosis and clinical management. Novel loci for investigation in the corresponding human disease studies have been identified and future work will begin to genetically link the conditions in dog and man.
Additional digital content not deposited electronically:
CD-ROM containing: SNPs discovered by next-generation sequencing in anal furunculosis, GWAS results files, meta-analysis results files, Sequenom primer sequences
Thesis main supervisor(s):
Thesis co-supervisor(s):
Thesis advisor(s):
Language:
en

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:180616
Created by:
Massey, Jonathan
Created:
31st October, 2012, 11:00:04
Last modified by:
Massey, Jonathan
Last modified:
9th December, 2014, 12:07:52

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