Genomic Heritability and Genome-Wide Association Studies of Plasma Metabolites in Crossbred Beef Cattle
Metabolites, substrates or products of metabolic processes, are involved in many biological functions, such as energy metabolism, signaling, stimulatory and inhibitory effects on enzymes and immunological defense. Metabolomic phenotypes are influenced by combination of genetic and environmental effects allowing for metabolome-genome-wide association studies (mGWAS) as a powerful tool to investigate the relationship between these phenotypes and genetic variants. The objectives of this study were to estimate genomic heritability and perform mGWAS and in silico functional enrichment analyses for a set of plasma metabolites in Canadian crossbred beef cattle. Thirty-three plasma metabolites and 45,266 single nucleotide polymorphisms (SNPs) were available for 475 animals. Genomic heritability for all metabolites was estimated using genomic best linear unbiased prediction (GBLUP) including genomic breed composition as covariates in the model. A single-step GBLUP implemented in BLUPF90 programs was used to determine SNP P values and the proportion of genetic variance explained by SNP windows containing 10 consecutive SNPs. The top 10 SNP windows that explained the largest genetic variation for each metabolite were identified and mapped to detect corresponding candidate genes. Functional enrichment analyses were performed on metabolites and their candidate genes using the Ingenuity Pathway Analysis software. Eleven metabolites showed low to moderate heritability that ranged from 0.09 ± 0.15 to 0.36 ± 0.15, while heritability estimates for 22 metabolites were zero or negligible. This result indicates that while variations in 11 metabolites were due to genetic variants, the majority are largely influenced by environment. Three significant SNP associations were detected for betaine (rs109862186), L-alanine (rs81117935), and L-lactic acid (rs42009425) based on Bonferroni correction for multiple testing (family wise error rate <0.05). The SNP rs81117935 was found to be located within the Catenin Alpha 2 gene (CTNNA2) showing a possible association with the regulation of L-alanine concentration. Other candidate genes were identified based on additive genetic variance explained by SNP windows of 10 consecutive SNPs. The observed heritability estimates and the candidate genes and networks identified in this study will serve as baseline information for research into the utilization of plasma metabolites for genetic improvement of crossbred beef cattle.