A genome-wide association study for somatic cell score using the Illumina high-density bovine beadchip identifies several novel QTL potentially related to mastitis susceptibility

Abstract

Mastitis is an inflammation-driven disease of the bovine mammary gland that occurs in response to physical damage or infection and is one of the most costly production-related diseases in the dairy industry worldwide. We performed a genome-wide association study (GWAS) to identify genetic loci associated with somatic cell score (SCS), an indicator trait of mammary gland inflammation. A total of 702 Holstein-Friesian bulls were genotyped for 777,962 single nucleotide polymorphisms (SNPs) and associated with SCS phenotypes. The SCS phenotypes were expressed as daughter yield deviations (DYD) based on a large number of progeny performance records. A total of 138 SNPs on 15 different chromosomes reached genome-wide significance (corrected p-value ≤ 0.05) for association with SCS (after correction for multiple testing). We defined 28 distinct QTL regions and a number of candidate genes located in these QTL regions were identified. The most significant association (p-value = 1.70 × 10(-7)) was observed on chromosome 6. This QTL had no known genes annotated within it, however, the Ensembl Genome Browser predicted the presence of a small non-coding RNA (a Y RNA gene) in this genomic region. This Y RNA gene was 99% identical to human RNY4. Y RNAs are a rare type of non-coding RNA that were originally discovered due to their association with the autoimmune disease, systemic lupus erythematosus. Examining small-RNA sequencing (RNAseq) data being generated by us in multiple different mastitis-pathogen challenged cell-types has revealed that this Y RNA is expressed (but not differentially expressed) in these cells. Other QTL regions identified in this study also encoded strong candidate genes for mastitis susceptibility. A QTL region on chromosome 13, for example, was found to contain a cluster of β-defensin genes, a gene family with known roles in innate immunity. Due to the increased SNP density, this study also refined the boundaries for several known QTL for SCS and mastitis.

Keywords: GWAS; Holstein-Friesian; SNP; mastitis; somatic cell score.

Figure 1

A Manhattan plot of genome-wide associations for somatic cell score in 702 Holstein-Friesian sires. The −log₁₀ of the uncorrected p-values is shown for each SNP (y-axis). The genome-wide significance threshold is indicated by a dashed line.

Figure 2

QTL region associated with SCS on chromosome 6. (A) Compares the associations from this study (Illumina BovineHD BeadChip) with those of a previous study (Meredith et al., 2012) of similar design but using a lower-density genotyping array (Illumina BovineSNP50 BeadChip). (B) Shows the associated region (associations from current study) in closer detail with significant SNPs indicated in blue and any SNP in moderate to strong linkage disequilibrium (r² ≥ 0.5) with a significant SNP indicated in red. (C) Shows the genes that are annotated in this region based on the UMD 3.1 assembly annotation from Ensembl. The genome-wide significance threshold is indicated by a dashed line.

Figure 3

QTL region associated with SCS on chromosome 13. (A) Compares the associations from this study (Illumina BovineHD BeadChip) with those of a previous study (Meredith et al., 2012) of similar design but using a lower-density genotyping array (Illumina BovineSNP50 BeadChip). (B) Shows the associated region (associations from current study) in closer detail with significant SNPs indicated in blue and any SNP in moderate to strong linkage disequilibrium (r² ≥ 0.5) with a significant SNP indicated in red. The genome-wide significance threshold is indicated by a dashed line.

Figure 4

QTL region associated with SCS on chromosome 17. (A) Compares the associations from this study (Illumina BovineHD BeadChip) with those of a previous study (Meredith et al., 2012) of similar design but using a lower-density genotyping array (Illumina BovineSNP50 BeadChip). (B) Shows the associated region (associations from current study) in closer detail with significant SNPs indicated in blue and any SNP in moderate to strong linkage disequilibrium (r² ≥ 0.5) with a significant SNP indicated in red. The genome-wide significance threshold is indicated by a dashed line.