A principal component regression based genome wide analysis approach reveals the presence of a novel QTL on BTA7 for MAP resistance in holstein cattle

Abstract

Bovine Johne's disease (JD), caused by Mycobacterium avium spp. paratuberculosis (MAP), causes significant losses to the dairy and beef cattle industries. Effective vaccination or therapeutic strategies against this disease are currently unavailable and infected animals either get culled or die due to clinical disease. An alternative strategy to manage the disease is to selectively breed animals with enhanced resistance to MAP infection. Therefore, the objective of this study was to identify genetic loci putatively associated with MAP infection in a resource population consisting of Holstein cattle using a genome-wide association approach. The BovineSNP50 BeadChip, containing 54,001 single nucleotide polymorphisms (SNPs), was used to genotype 232 animals with known MAP infection status. Since, traditional case-control analytical techniques are based on single-marker analysis and do not account for the existence of linkage disequilibrium (LD) between markers, we used a novel principal component regression approach, where each SNP was fit in a logistic regression model, along with principal components of other SNPs on the same chromosome showing association with the trait, as covariates. Such an approach allowed us to account for the LD that exists between multiple markers showing an association on the same chromosome. Our analysis revealed the presence of at least 12 genomic regions on BTA1, 5, 6, 7, 10, 11 and 14 that were associated with the MAP infection status of our resource population. A brief description of these genomic regions, and a discussion of the analysis used in this study, have been presented.

Phenotype definition is a main point in genome-wide association studies for bovine Mycobacterium avium ssp. paratuberculosis infection status

“…None of these genes were found in previous published GWA studies (summarized in Supplementary Table S1). Also there is no functional candidate gene described in the literature within 1 Mbp region of the SNPs in the present study (Settles et al, 2009;Minozzi et al, 2010;Pant et al, 2010;Kirkpatrick et al, 2011;Minozzi et al, 2012;van Hulzen et al, 2012). This supports once more the conclusion that paratuberculosis is probably affected by a large number of genes.…”

“…On the other hand it could be an effect of the unclear definition of the animal phenotype, because GWA-studies based on phenotype definition by different test methods identify different genes (Minozzi et al, 2012). Most GWA studies used milk or blood ELISA for phenotyping (Minozzi et al, 2010;Pant et al, 2010;RuizLarranaga et al, 2010b;Kirkpatrick et al, 2011;Minozzi et al, 2012). ELISA may identify genes which are involved in the immune response to the agent, whereas bacterial culture of bacteria in feces or tissue will identify genetic loci, which are involved in the persistence of the MAP infection at different stages of the disease (Minozzi et al, 2012), the development of the granulomatous enteritis and the release of MAP into the feces.…”

“…In this study, regions on BTA 3 and 9 were identified with a high significance to MAP status tested by MAP culture in feces and tissue in US Holsteins. In different GWA studies several associations were found on different chromosomes (Minozzi et al, 2010;Pant et al, 2010;Kirkpatrick et al, 2011;Minozzi et al, 2012;van Hulzen et al, 2012), summarized in Supplementary Table S1. These studies provide in general evidence for the existence of genomic regions associated with MAP infection in dairy cows.…”

Estimating host genetic effects on susceptibility and infectivity to infectious diseases and their contribution to response to selection

“…This suggests that genetic variation present in the direct effect of susceptibility and indirect effect of individual's infectivity contribute to the total heritable variation in R 0 . A number of genome-wide association studies have reported the existence of single nucleotide polymorphisms (SNPs) that are associated with susceptibility to different infectious diseases (Pant et al, 2010;Sherlock et al, 2013;. Heritability estimates for susceptibility to infectious diseases also indicate the presence of exploitable genetic variation in susceptibility to infectious diseases Gonda et al, 2006).…”

“…SNPs, which are the most common source of genetic variation that have been used in genome-wide association studies (GWAS) in order to identify genes that are associated with a number of quantitative traits (Cochran et al, 2013;Mancini et al, 2013;Duchemin et al, 2014). GWAS have also been applied to identify genes that are associated with susceptibility to various infectious diseases (Pant et al, 2010;Sherlock et al, 2013;LaRose et al, 2015). In addition to their application to identify genes associated with individual susceptibility to infectious diseases, GWAS can also be used to identify genes that are associated with individual infectivity, from which the gene effects on R 0 can be estimated.…”