The genetic architecture of milk ELISA scores as an indicator of Johne's disease (paratuberculosis) in dairy cattle

Abstract

Johne's disease (or paratuberculosis), caused by Mycobacterium avium ssp. paratuberculosis (MAP) infection, is a globally prevalent disease with severe economic and welfare implications. With no effective treatment available, understanding the role of genetics influencing host infection status is essential to develop selection strategies to breed for increased resistance to MAP infection. The main objectives of this study were to estimate genetic parameters for the MAP-specific antibody response using milk ELISA scores in Canadian Holstein cattle as an indicator of resistance to Johne's disease, and to unravel genomic regions and candidate genes significantly associated with MAP infection. After data editing, 168,987 milk ELISA records from 2,306 herds, obtained from CanWest Dairy Herd Improvement, were used for further analyses. Variance and heritability estimates for MAP infection status were determined using univariate linear animal models under 3 scenarios: (a) SCEN1: the complete data set (all herds); (b) SCEN2: herds with at least one suspect or test-positive animal (ELISA optical density ≥0.07); and (c) SCEN3: herds with at least one test-positive animal (ELISA optical density ≥0.11). Heritability estimates were calculated as 0.066, 0.064, and 0.063 for SCEN1, SCEN2, and SCEN3, respectively. The correlations between estimated breeding values for resistance to MAP infection and other economically important traits, when significant, were favorable and of low magnitude. Genome-wide association analyses identified important genomic regions on Bos taurus autosome (BTA)1, BTA7, BTA9, BTA14, BTA15, BTA17, BTA19, and BTA25 showing significant association with MAP infection status. These regions included 2 single nucleotide polymorphisms located 2 kb upstream of positional candidate genes CD86 and WNT9B, which play key roles in host immune response and tissue homeostasis. This study revealed the genetic architecture of MAP infection in Canadian Holstein cattle as measured by milk ELISA scores by estimating genetic parameters along with the identification of genomic regions potentially influencing MAP infection status. These findings will be of significant value toward implementing genetic and genomic evaluations for resistance to MAP infection in Holstein cattle.

Candidate genes associated with the heritable humoral response to Mycobacterium avium ssp. paratuberculosis in dairy cows have factors in common with gastrointestinal diseases in humans

“…Expression of ZBTB20 has been observed in human tissues relevant to Johne's disease, such as the colon, duodenum, lymph nodes, small intestine, and spleen (Fagerberg et al, 2014). Moreover, ZBTB20 was also identified as a candidate gene in the genome-wide association study conducted by Brito et al (2018) in dairy cows, further substantiating the evidence that ZBTB20 could indeed be associated with the resistance status of cattle to MAP.…”

“…Furthermore, the rho kinase signal pathway has previously been implicated in inflammatory bowel disease (IBD) in humans, playing roles in intestinal barrier damage, abnormal immune response, and intestinal fibrosis (Huang et al, 2015). Brito et al (2018) also identified KALRN as a candidate gene in an independent population of ELISA-tested Canadian Holstein cattle. Thus, it is not unrealistic to hypothesize that KALRN plays an important role in the aforementioned processes in cattle susceptible to Johne's disease.…”

“…This influence may in part give rise to the fact that previous studies have implicated all Bos taurus autosomes as having an association with bovine paratuberculosis, yet little consistency has been observed among the reported genomic locations of these studies. Other factors that must be considered as contributors to this lack of coherence include the low heritability of the trait, inconsistent methods to classify MAP-positive or -negative animals, and divergent statistical methodologies employed on varying sample sizes of different cattle populations (Brito et al, 2018). Specific to the present study, another factor contributing to spurious results is the error in genotype imputation from sequence data.…”

“…All candidate genes have been shown to exhibit an expression profile in the bovine colon, duodenum, ileum, spleen, and lymph nodes (Harhay et al, 2010). As stated by Brito et al (2018), resistance or susceptibility to MAP infection appears to be a highly polygenic trait, reflecting the nature of bovine paratuberculosis, which is, indeed, a highly complex trait. As such, the environmental influence on the manifestation of the trait must not be ignored.…”

Identification of the ABCC4, IER3, and CBFA2T2 candidate genes for resistance to paratuberculosis from sequence-based GWAS in Holstein and Normande dairy cattle

“…As recently reviewed by Brito et al [6], various studies have shown the role of host genetics in resistance to MAP and have estimated heritability values for this trait between 0.03 and 0.27. In addition, numerous genomewide association studies (GWAS) have been conducted using genotyping of single-nucleotide polymorphisms (SNPs) at low [7], medium [8][9][10][11][12][13][14], or high [6,15,16] densities as well as whole-genome sequences [17,18] imputed from data of the 1000 Bull Genomes project [19]. These GWAS analyses have led to the identification of quantitative trait loci (QTL) associated with resistance/susceptibility to MAP on all Bos taurus (BTA) autosomes, with the most frequently identified QTL located on BTA1, 6, 7, and 23.…”