Genome-wide association analysis for susceptibility to infection by Mycobacterium avium ssp. paratuberculosis in US Holsteins

Abstract

Paratuberculosis, or Johne's disease, is a chronic, granulomatous, gastrointestinal tract disease of cattle and other ruminants caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). Control of Johne's disease is based on programs of testing and culling animals positive for infection with MAP and concurrently modifying management to reduce the likelihood of infection. The current study was motivated by the hypothesis that genetic variation in host susceptibility to MAP infection can be dissected and quantifiable associations with genetic markers identified. Two separate GWAS analyses were conducted, the first using 897 genotyped Holstein artificial insemination sires with phenotypes derived from incidence of MAP infection among daughters based on milk ELISA testing records. The second GWAS analysis was a case-control design using US Holstein cows phenotyped for MAP infection by serum ELISA or fecal culture tests. Cases included cows positive for either serum ELISA, fecal culture, or both. Controls consisted of animals negative for all tests conducted. A total of 376 samples (70 cases and 306 controls) from a University of Minnesota Johne's management demonstration project and 184 samples (76 cases and 108 controls) from a Michigan State University study were used. Medium-density (sires) and high-density (cows) genotype data were imputed to full genome sequence for the analyses. Marker-trait associations were analyzed using the single-step (ss)GWAS procedure implemented in the BLUPF90 suite of programs. Evidence of significant genomic contributions for susceptibility to MAP infection were observed on multiple chromosomes. Results were combined across studies in a meta-analysis, and increased support for genomic regions on BTA7 and BTA21 were observed. Gene set enrichment analysis suggested pathways for antigen processing and presentation, antimicrobial peptides and natural killer cell-mediated cytotoxicity are relevant to variation in host susceptibility to MAP infection, among others. Genomic prediction was evaluated using a 5-fold cross-validation, and moderate correlations were observed between genomic breeding value predictions and daughter averages (~0.43 to 0.53) for MAP infection in testing data sets. These results suggest that genomic selection against susceptibility to MAP infection is feasible in Holstein cattle.

New insights into the genetic resistance to paratuberculosis in Holstein cattle via single-step genomic evaluation

“…This discrepancy is not very surprising given that there has been little agreement among the numerous GWAS analyses that have been conducted to date (using SNPs at different densities) for resistance to JD. The genomic region located in the vicinity of the major histocompatibility complex on chromosome 23 is the only QTL that has been detected by almost all published GWAS, in particular the most recent ones that were performed with high-density SNP genotypes or imputed whole-genome sequences [ 8 , 9 , 28 , 29 ]. Most of the other genomic regions detected in this study were previously described as affecting resistance to JD in at least one GWAS.…”

“…Autophagy is a cellular process that can eliminate intracellular pathogens, including bacteria. Moreover, the ATGD4 gene is known to be associated with resistance to bovine paratuberculosis [ 9 ] and human Crohn’s disease [ 34 ], which is a chronic inflammatory bowel disease with a possible link to paratuberculosis. Silencing of the LRP1 gene, located in the QTL region on chromosome 5, has been found to exacerbate inflammatory response in mice [ 35 ].…”

“…Such genomic predictions can be of great help to identify cows at high risk of infection. As mentioned in the “ Background ” section, only one prior study has estimated the accuracy of genomic predictions for resistance to JD using cross-validation [ 9 ]. Those authors estimated correlations between genomic predictions for bulls and daughter averages for MAP infection, and obtained values ranging from 0.43 to 0.53.…”

“…Although these results are not all consistent (probably due to differences in the study designs, e.g., the population used, the definition of the resistance phenotype, the disease prevalence, or the detection power), overall, they suggest that genetics may help to control the disease. However, apart from a very recent study that estimated the accuracy of genomic predictions [ 9 ], little effort has been made to investigate the possibility of predicting resistance to JD from genomic data.…”

A Machine Learning Approach Reveals a Microbiota Signature for Infection with Mycobacterium avium subsp. paratuberculosis in Cattle

“…To overcome the limitation of high costs and time-consuming diagnoses based on bacterial culture, several culture-independent methods have been developed, such as fecal PCR ( 8 ) and enzyme-linked immunosorbent assay (ELISA) ( 9 ). Fecal PCR can detect the infectious state with high sensitivity, but there are still challenges, such as PCR inhibitors in feces ( 10 ), insufficient primer specificity ( 11 ), and low-level intermittent shedding during the subclinical stage ( 12 ).…”