Gene set enrichment analysis of bovine respiratory disease complex SNP data in feedlot cattle

Abstract Text: Bovine Respiratory Disease Complex (BRDC) is responsible for annual deaths of more than 350,000 feedlot cattle and estimated losses of over $1 billion in the US. The objective of this study was to use gene set enrichment analysis of SNP data (GSEA-SNP) to identify pathways associated with susceptibility to BRDC in Bos taurus feedlot cattle. Cattle were sampled from commercial feedlots in Colorado and Washington and cases were determined using the McGuirk diagnostic system. Approximately equal numbers of steers (933) and heifers (935) and cases (936) and controls (932) were genotyped with the Illumina BovineHD BeadChip and analyzed using an additive model with breed (Angus, Red Angus, Crossbred, Charolais and Hereford), days to pen removal, month and location as covariates in the genome wide association analysis (GWAA). EIGENSTRAT principal component (PC) analysis was used to correct for population stratification using the first 10 PC resulting in l= 1.03. GWAA was followed by GSEA-SNP utilizing 4,388 pathways from Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes, Reactome, Biocarta and Panther. Haplotype block size was estimated and averaged across breeds to determine the size of the interval harboring each gene in which to search for a SNP that would serve as the proxy for the gene. The most significant SNP from the GWAA that was located within 7kb of each gene was used as the proxy for each of the 19,723 genes mapped in the UMD 3.1 assembly. For each gene set, the significance value was calculated using the null distribution generated from 10,000 phenotype-based permutations. Enrichment scores (ES) were calculated using running sum statistics. Five GO gene sets had normalized ES > 3 and were found to be associated with susceptibility to BRDC: GO:0005887 Integral Component of Plasma Membrane, GO:0031324 Negative Regulation of Cellular Protein Metabolic Process, GO:0005496 Steroid Binding, GO:0030162 Regulation of Proteolysis and GO:0008277 Regulation of G Protein Coupled Receptor Protein Signaling Pathway. No other gene sets were found to be associated with BRDC susceptibility. Of the 228 leading edge genes, 79 were differentially expressed between cases and controls and represent putative BRDC functional candidate genes which will be further investigated to determine how they may be best used in the selection of feedlot cattle that are more resistant to BRDC. 

Keywords: GSEA-SNP, bovine respiratory disease complex