A genome-wide association study for genetic susceptibility to Mycobacterium bovis infection in dairy cattle identifies a susceptibility QTL on chromosome 23

AbstractBackgroundBovine tuberculosis (bTB) infection in cattle is a significant economic concern in many countries, with annual costs to the UK and Irish governments of approximately €190 million and €63 million, respectively, for bTB control. The existence of host additive and non-additive genetic components to bTB susceptibility has been established.MethodsTwo approaches i.e. single-SNP (single nucleotide polymorphism) regression and a Bayesian method were applied to genome-wide association studies (GWAS) using high-density SNP genotypes (n = 597,144 SNPs) from 841 dairy artificial insemination (AI) sires. Deregressed estimated breeding values for bTB susceptibility were used as the quantitative dependent variable. Network analysis was performed using the quantitative trait loci (QTL) that were identified as significant in the single-SNP regression and Bayesian analyses separately. In addition, an identity-by-descent analysis was performed on a subset of the most prolific sires in the dataset that showed contrasting prevalences of bTB infection in daughters.ResultsA significant QTL region was identified on BTA23 (P value >1 × 10−5, Bayes factor >10) across all analyses. Sires with the minor allele (minor allele frequency = 0.136) for this QTL on BTA23 had estimated breeding values that conferred a greater susceptibility to bTB infection than those that were homozygous for the major allele. Imputation of the regions that flank this QTL on BTA23 to full sequence indicated that the most significant associations were located within introns of the FKBP5 gene.ConclusionsA genomic region on BTA23 that is strongly associated with host susceptibility to bTB infection was identified. This region contained FKBP5, a gene involved in the TNFα/NFκ-B signalling pathway, which is a major biological pathway associated with immune response. Although there is no study that validates this region in the literature, our approach represents one of the most powerful studies for the analysis of bTB susceptibility to date.

[1]  R. Fernando,et al.  Genomic prediction of simulated multibreed and purebred performance using observed fifty thousand single nucleotide polymorphism genotypes. , 2010, Journal of animal science.

[2]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[3]  A. Green,et al.  Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation. , 2013, American journal of human genetics.

[4]  A. Hamvas,et al.  An intronic ABCA3 mutation responsible for respiratory disease , 2012, Pediatric Research.

[5]  C. Khor,et al.  Host-pathogen interactions revealed by human genome-wide surveys. , 2012, Trends in genetics : TIG.

[6]  S. Brotherstone,et al.  Evidence of genetic resistance of cattle to infection with Mycobacterium bovis. , 2010, Journal of dairy science.

[7]  S. Brotherstone,et al.  Genetics of tuberculosis in Irish Holstein-Friesian dairy herds. , 2009, Journal of dairy science.

[8]  H. Kadarmideen,et al.  Polymorphisms of the SLC11A1 gene and resistance to bovine tuberculosis in African Zebu cattle. , 2011, Animal genetics.

[9]  J. Woolliams,et al.  Bovine tuberculosis: the genetic basis of host susceptibility , 2010, Proceedings of the Royal Society B: Biological Sciences.

[10]  Y. Chang,et al.  Genetic variation of Mycobacterium avium ssp. paratuberculosis infection in US Holsteins. , 2006, Journal of dairy science.

[11]  B. Browning,et al.  A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. , 2009, American journal of human genetics.

[12]  M. Martin,et al.  Tissue distribution and abundance of human FKBP51, and FK506-binding protein that can mediate calcineurin inhibition. , 1997, Biochemical and biophysical research communications.

[13]  K. Zilles,et al.  Phenotype of the taurine transporter knockout mouse. , 2007, Methods in enzymology.

[14]  S. More,et al.  Genetic variation in serological response to Mycobacterium avium subspecies paratuberculosis and its association with performance in Irish Holstein–Friesian dairy cows , 2010 .

[15]  S. Gordon,et al.  High Prevalence and Increased Severity of Pathology of Bovine Tuberculosis in Holsteins Compared to Zebu Breeds under Field Cattle Husbandry in Central Ethiopia , 2007, Clinical and Vaccine Immunology.

[16]  Julian Parkhill,et al.  The complete genome sequence of Mycobacterium bovis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. M. Smith,et al.  A whole genome association analysis identifies loci associated with Mycobacterium avium subsp. paratuberculosis infection status in US holstein cattle. , 2009, Animal genetics.

[18]  D. McMurray,et al.  Pathologic findings and association of Mycobacterium bovis infection with the bovine NRAMP1 gene in cattle from herds with naturally occurring tuberculosis. , 2000, American journal of veterinary research.

[19]  J. Woolliams,et al.  Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis , 2022 .

[20]  G. B. Mourão,et al.  Admixture mapping of tuberculosis and pigmentation-related traits in an African–European hybrid cattle population , 2015, Front. Genet..

[21]  Robin Thompson,et al.  ASREML user guide release 1.0 , 2002 .

[22]  S. More,et al.  The role of badgers in the epidemiology of Mycobacterium bovis infection (tuberculosis) in cattle in the United Kingdom and the Republic of Ireland: current perspectives on control strategies , 2014, Veterinary medicine.

[23]  R. Fernando,et al.  Deregressing estimated breeding values and weighting information for genomic regression analyses , 2009, Genetics Selection Evolution.

[24]  E. de Wit,et al.  Past, present and future directions in human genetic susceptibility to tuberculosis. , 2010, FEMS immunology and medical microbiology.

[25]  S. More,et al.  Variance components for susceptibility to Mycobacterium bovis infection in dairy and beef cattle , 2014, Genetics Selection Evolution.

[26]  J. Vermeersch,et al.  Towards eradication of bovine tuberculosis in the European Union. , 2006, Veterinary microbiology.

[27]  S. More,et al.  Bovine tuberculosis trends in the UK and the Republic of Ireland, 1995–2010 , 2013, Veterinary Record.

[28]  R. Smith-Coggins,et al.  Gender-associated differences in emergency department pain management. , 1995, Annals of emergency medicine.

[29]  A. Ruffino-Netto.  [Tuberculin test]. , 1979, AMB : revista da Associacao Medica Brasileira.

[30]  Karin Meyer,et al.  WOMBAT—A tool for mixed model analyses in quantitative genetics by restricted maximum likelihood (REML) , 2007, Journal of Zhejiang University SCIENCE B.

[31]  W. Dietrich,et al.  Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  F. Strozzi,et al.  Genetic Loci Involved in Antibody Response to Mycobacterium avium ssp. paratuberculosis in Cattle , 2010, PloS one.

[33]  K. Meyer,et al.  “SNP Snappy”: A Strategy for Fast Genome-Wide Association Studies Fitting a Full Mixed Model , 2012, Genetics.

[34]  D. Berry,et al.  Within- and across-breed imputation of high-density genotypes in dairy and beef cattle from medium- and low-density genotypes. , 2014, Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie.

[35]  R W Sweeney,et al.  Transmission of paratuberculosis. , 1994, The Veterinary clinics of North America. Food animal practice.

[36]  H. Whittle,et al.  Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. , 1998, The New England journal of medicine.

[37]  B. Maher.  Personal genomes: The case of the missing heritability , 2008, Nature.

[38]  R. Veerkamp,et al.  Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle , 2014, Nature Genetics.

[39]  J. A. Bishop,et al.  A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. , 2001, Human molecular genetics.

[40]  B. Browning,et al.  Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. , 2007, American journal of human genetics.

[41]  S. Nielsen,et al.  Genetic variation and heritability of the antibody response to Mycobacterium avium subspecies paratuberculosis in Danish Holstein cows. , 2004, Journal of dairy science.

[42]  Karin Breuer,et al.  InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation , 2012, Nucleic Acids Res..

[43]  D. Bradley,et al.  A Genome Wide Association Scan of Bovine Tuberculosis Susceptibility in Holstein-Friesian Dairy Cattle , 2012, PloS one.

[44]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[45]  H. Vordermeier,et al.  Ante mortem diagnosis of tuberculosis in cattle: a review of the tuberculin tests, gamma-interferon assay and other ancillary diagnostic techniques. , 2006, Research in veterinary science.

[46]  F. Strozzi,et al.  Meta-Analysis of Two Genome-Wide Association Studies of Bovine Paratuberculosis , 2012, PloS one.

[47]  J. Kearney,et al.  Associations between the K232A polymorphism in the diacylglycerol-O-transferase 1 (DGAT1) gene and performance in Irish Holstein-Friesian dairy cattle , 2010 .

[48]  M. Goddard,et al.  Prediction of total genetic value using genome-wide dense marker maps. , 2001, Genetics.