A genome wide association scan of bovine tuberculosis susceptibility in Holstein-Friesian dairy cattle

Abstract

Background: Bovine tuberculosis is a significant veterinary and financial problem in many parts of the world. Although many factors influence infection and progression of the disease, there is a host genetic component and dissection of this may enlighten on the wider biology of host response to tuberculosis. However, a binary phenotype of presence/absence of infection presents a noisy signal for genomewide association study.

Methodology/principal findings: We calculated a composite phenotype of genetic merit for TB susceptibility based on disease incidence in daughters of elite sires used for artificial insemination in the Irish dairy herd. This robust measure was compared with 44,426 SNP genotypes in the most informative 307 subjects in a genome wide association analysis. Three SNPs in a 65 kb genomic region on BTA 22 were associated (i.e. p<10(-5), peaking at position 59588069, p = 4.02×10(-6)) with tuberculosis susceptibility.

Conclusions/significance: A genomic region on BTA 22 was suggestively associated with tuberculosis susceptibility; it contains the taurine transporter gene SLC6A6, or TauT, which is known to function in the immune system but has not previously been investigated for its role in tuberculosis infection.

Figure 1. Multidimensional scaling (MDS) analysis of an Identity by State (IBS) matrix of 986 samples, divided into two clusters which reflect differing proportions of Holstein and Friesian ancestry.

Both phenotypes and genotypes were adjusted for the population structure before analysis.

Figure 2. Manhattan plot displaying the results (−log 10 of p-values) of the genome wide scan with respect to genomic position.

Three SNPs on chromosome 22 attain chromosome wide significance and are indicated with red dots.

Figure 3. Q-Q plot of observed p-values against expected p values.

Figure 4. Scatter plot of the p values on chromosome 22 and a 1 Mb region surrounding the three most significant SNPs.

Significance (−log 10 of p-values) is plotted against position along the chromosome and the three SNPs above the threshold of chromosome wide significance (the red line) are indicated in red. The 1 Mb region surrounding these SNPs is shown in more detail and superimposed on the genes found in the region. One of the SNPs lies within the first intron of the gene SLC6A6 and the other two are upstream (plot generated using build Btau4.2 on animalgenome.org).