RT Journal Article
SR Electronic
T1 Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 143404
DO 10.1101/143404
A1 Hubert Pausch
A1 Reiner Emmerling
A1 Birgit Gredler-Grandl
A1 Ruedi Fries
A1 Hans D Daetwyler
A1 Michael E Goddard
YR 2017
UL http://biorxiv.org/content/early/2017/05/29/143404.1.abstract
AB Background Genotyping and whole-genome sequencing data have been collected in many cattle breeds. The compilation of large reference panels facilitates to impute sequence variant genotypes for animals that have been genotyped using dense genotyping arrays. Association studies with imputed sequence variant genotypes allow to characterizing quantitative trait loci (QTL) at nucleotide resolution particularly when individuals from several breeds are included in the mapping populations.Results We imputed genotypes for more than 28 million sequence variants in 17,229 animals of the Braunvieh (BV), Fleckvieh (FV) and Holstein (HOL) cattle breeds. Within-breed association tests between imputed sequence variant genotypes and fat and protein percentages in milk uncovered between six and thirteen QTL (P<1e-8) per breed. Eight QTL were significant in more than one breed. Meta-analysis of the association studies across three breeds identified 25 QTL including six that were not significant in the within-breed association studies. Two causal missense mutations in the ABCG2 (p.Y581S, rs43702337, P=4.3e-34) and GHR (p.F279Y, rs385640152, P=1.6e-74) genes were the top variants at two QTL on chromosomes 6 and 20. Another causal missense mutation in the DGAT1 gene (p.A232K, rs109326954, P=8.4e-1436) was the second top variant at a QTL on chromosome 14 but its allelic substitution effects were not consistent across three breeds analyzed. The conflicting allelic substitution effects resulted from flaws in the imputed genotypes due to the use of a multi-breed reference population for genotype imputation.Conclusions Many QTL for milk production traits segregate across breeds. Meta-analysis of association studies across breeds has greater power to detect QTL than within-breed association studies. True causal mutations can be readily detected among the most significantly associated variants when the accuracy of imputation is high. Validating the effect of known causal variants is useful to assess the ability to detect true causal mutations in association studies with imputed sequence variants.BVBraunviehFPfat percentageFVFleckviehHDhigh densityHOLHolsteinLDlinkage disequilibriumMAFminor allele frequencyPPprotein percentageQTLquantitative trait lociSNPsingle nucleotide polymorphism