Distinguishing pleiotropy from linked QTL between milk production traits and mastitis resistance in Nordic Holstein cattle

Abstract

Background: Production and health traits are central in cattle breeding. Advances in next-generation sequencing technologies and genotype imputation have increased the resolution of gene mapping based on genome-wide association studies (GWAS). Thus, numerous candidate genes that affect milk yield, milk composition, and mastitis resistance in dairy cattle are reported in the literature. Effect-bearing variants often affect multiple traits. Because the detection of overlapping quantitative trait loci (QTL) regions from single-trait GWAS is too inaccurate and subjective, multi-trait analysis is a better approach to detect pleiotropic effects of variants in candidate genes. However, large sample sizes are required to achieve sufficient power. Multi-trait meta-analysis is one approach to deal with this problem. Thus, we performed two multi-trait meta-analyses, one for three milk production traits (milk yield, protein yield and fat yield), and one for milk yield and mastitis resistance. Results: For highly correlated traits, the power to detect pleiotropy was increased by multi-trait meta-analysis compared with the subjective assessment of overlapping of single-trait QTL confidence intervals. Pleiotropic effects of lead single nucleotide polymorphisms (SNPs) that were detected from the multi-trait meta-analysis were confirmed by bivariate association analysis. The previously reported pleiotropic effects of variants within the DGAT1 and MGST1 genes on three milk production traits, and pleiotropic effects of variants in GHR on milk yield and fat yield were confirmed. Furthermore, our results suggested that variants in KCTD16, KCNK18 and ENSBTAG00000023629 had pleiotropic effects on milk production traits. For milk yield and mastitis resistance, we identified possible pleiotropic effects of variants in two genes, GC and DGAT1. Conclusions: Multi-trait meta-analysis improves our ability to detect pleiotropic interactions between milk production traits and identifies variants with pleiotropic effects on milk production traits and mastitis resistance. In particular, this should contribute to better understand the biological mechanisms that underlie the unfavorable genetic correlation between milk yield and mastitis.

Estimated genetic parameters for all genetically evaluated traits in Canadian Holsteins

“…Regarding production traits, the 5 highest genetic correlations were observed for MY and PY (0.86 ± 0.01), Fat% and Protein% (0.66 ± 0.01), FY and PY (0.64 ± 0.01), MY and Protein% (−0.57 ± 0.01), and FY and Fat% (0.49 ± 0.01; Table 3). Cai et al (2020) also reported high genetic correlations between MY and PY (0.78), FY and MY (0.40), and FY and PY (0.56). Likewise, Kadarmideen et al (2003) and Martin et al (2019) reported similar results as in this study.…”

A 12 kb multi-allelic copy number variation encompassing a GC gene enhancer is associated with mastitis resistance in dairy cattle

“…One of these studies investigated, albeit unsuccessfully, whether one of the non-coding candidate SNP obtained from the GWAS was associated with GC expression, leaving the functional mechanisms underlying this association elusive [13]. Interestingly, the proposed candidate SNPs showed antagonistic allele effects for milk yield (MY) (the high CM resistance allele was linked to low MY, and vice versa [7,13,16]), and one study concluded that a single pleiotropic variant regulates both of the traits [17]. Furthermore, this locus harbours QTL for many traits including body conformation, fertility, and longevity [11,15,[18][19][20][21][22], implying pleiotropy, which remains to be investigated.…”

Genome-Wide Scanning for Signatures of Selection Revealed the Putative Genomic Regions and Candidate Genes Controlling Milk Composition and Coat Color Traits in Sahiwal Cattle

“…In our study, additionally one more candidate gene located on BTA 9 and related to milk production was observed (Mustafa et al, 2018). Multi-trait meta-analysis in Nordic cattle detected several loci with pleiotropic effects on milk production and mastitis resistance (Cai et al, 2020). We identified another candidate gene Zinc finger protein (ZNF469), associated with milk production and mastitis resistance in cattle in the intergenic region of BTA 18.…”