Gene Set Enrichment Analysis of Bovine Respiratory Disease SNP Genotypic Data

Bovine Respiratory Disease (BRD) is one of the most common causes of premature death of cattle in the U.S. It is a complex disease that involves several viral and bacterial pathogens that are opportunistic during times of stress. To elucidate the genetic basis of the disease, 1376 BRD cases and 1380 controls from Holstein herds in California and New Mexico were genotyped using the Illumina Bovine HD chip. BRD status (case/control) was defined by a standardized calf-BRD health scoring system (McGuirk 2007). Genome-wide association analysis (GWAS) was conducted with the genotypic test in GenGen (Wang et al. 2007). GWAS was followed by Gene Set Enrichment Analysis of SNP data utilizing Bos taurus pathways from GO, KEGG, Panther, Reactome, and Metacyc. SNPs were mapped to the genes located within the closest proximity. The null distribution of the GSEA test statistic was approximated using 10,000 permutations. Four gene sets (GO:0043903 – regulation of symbiosis, encompassing mutualism through parasitism, GO:0030949 – positive regulation of vascular endothelial growth factor receptor signaling pathway, GO:0031334 – positive regulation of protein complex assembly, and P00026 – heterometric G-protein signaling pathway) were found to be associated with susceptibility to BRD (FDR<0.25). These pathways include 270 unique genes; 87 of which contributed to an increase in the GSEA test statistic and represent putative functional candidate genes involved in BRD susceptibility. However, none of the 87 genes were identified by GWAS alone. Identification of genes important in BRD susceptibility will facilitate the selection of animals that are less likely to become diseased.