Identification of genes associated with susceptibility to mycobacterium avium ssp. paratuberculosis (Map) tissue infection in Holstein cattle using gene set enrichment analysis-SNP

Authors: KISE, JENNIFER - Washington State University; NEUPANE, MAHESH - Washington State University; White, Stephen; NEIBERGS, HOLLY - Washington State University

Submitted to: Mammalian Genome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2017
Publication Date: 8/31/2018
Citation: Kise, J.N., Neupane, M., White, S.N., Neibergs, H.N. 2018. Identification of genes associated with susceptibility to mycobacterium avium ssp. paratuberculosis (Map) tissue infection in Holstein cattle using gene set enrichment analysis-SNP. Mammalian Genome. 29(7-8):539-549. https://doi.org/10.1007/s00335-017-9725-4.
DOI: https://doi.org/10.1007/s00335-017-9725-4

Interpretive Summary: Johne's disease is a progressive disease of ruminants that costs hundreds of millions of dollars annually for U.S. agriculture and results from gut infection by the intracellular pathogen Mycobacterium avium subspecies paratuberculosis (Map). While multiple studies have identified cattle genes associated with Johne's disease and Map infection, two research needs have been validation of genes across multiple animal populations and use of sensitive techniques to detect genes with moderate association as well as those with very large impacts. We used gene set enrichment analysis with single nucleotide polymorphism data (GSEA-SNP) in multiple populations to address these issues. Thirteen gene sets were enriched in these analyses and all had functions that relate to nuclear factor kappa-beta, which is a critical component of gut immune responses and implicated in responses to other mycobacterial diseases. In addition, many cellular transporters were identified in these gene sets, suggesting cellular control of nutrient availability may be a helpful strategy in limiting Map infection. Gene sets and genes moderately associated with Map infection expand understanding of genes involved in susceptibility to mycobacterial infection and could be used in genomic selection to allow producers to select for less susceptible cattle, lower the prevalence of the disease, and reduce economic losses.

Technical Abstract: Multiple genome-wide association analyses have investigated susceptibility to bovine paratuberculosis, but few loci have been identified across independent cattle populations. A SNP-based gene set enrichment analysis (GSEA-SNP) allows expanded identification of genes with moderate effects on a trait through the enrichment of gene sets instead of identifyingonly few loci with large effects. Therefore, the objective of this study was to identify genes that were moderately associated with Mycobacterium avium ssp. paratuberculosis (Map) tissue infection using GSEA-SNP in Holstein cattle from the Pacific Northwest (PNW; n = 205) and from the PNW and Northeast (PNW+NE; n = 245) animal sets which were previously genotyped with the Illumina BovineSNP50 Beadchip. The GSEA-SNP utilized 4,389 gene sets from five databases: Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome, Biocarta, and Panther. For each annotated gene in the UMD3.1 assembly (n = 19,723), the most significant SNP within each gene and its surrounding region (10kb up- and downstream) was selected as a proxy for that gene. Any gene set with a normalized enrichment score > 2.5 was considered enriched. Thirteen gene sets (8 PNW GSEA-SNP; 5 PNW+NE) were enriched in these analyses and all had functions that relate to nuclear factor kappa-beta, which is critical to gut immune responses and implicated in responses to other mycobacterial diseases. In addition, many cellular transporters were identified in these gene sets, suggesting cellular control of nutrient availability may be a helpful strategy in limiting Map infection. Gene sets and genes moderately associated with Map infection expand understanding of genes involved in susceptibility to mycobacterial infection and could be used in genomic selection to allow producers to select for less susceptible cattle, lower the prevalence of the disease, and reduce economic losses.