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Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution
BACKGROUND: Genotyping and whole-genome sequencing data have been generated for hundreds of thousands of cattle. International consortia used these data to compile imputation reference panels that facilitate the imputation of sequence variant genotypes for animals that have been genotyped using dens...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680815/ https://www.ncbi.nlm.nih.gov/pubmed/29121857 http://dx.doi.org/10.1186/s12864-017-4263-8 |
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author | Pausch, Hubert Emmerling, Reiner Gredler-Grandl, Birgit Fries, Ruedi Daetwyler, Hans D. Goddard, Michael E. |
author_facet | Pausch, Hubert Emmerling, Reiner Gredler-Grandl, Birgit Fries, Ruedi Daetwyler, Hans D. Goddard, Michael E. |
author_sort | Pausch, Hubert |
collection | PubMed |
description | BACKGROUND: Genotyping and whole-genome sequencing data have been generated for hundreds of thousands of cattle. International consortia used these data to compile imputation reference panels that facilitate the imputation of sequence variant genotypes for animals that have been genotyped using dense microarrays. Association studies with imputed sequence variant genotypes allow for the characterization of quantitative trait loci (QTL) at nucleotide resolution particularly when individuals from several breeds are included in the mapping populations. RESULTS: We imputed genotypes for 28 million sequence variants in 17,229 cattle of the Braunvieh, Fleckvieh and Holstein breeds in order to compile large mapping populations that provide high power to identify QTL for milk production traits. 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 of the detected QTL were significant in more than one breed. We combined the results across breeds using meta-analysis and identified a total of 25 QTL including six that were not significant in the within-breed association studies. Two 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 QTL on chromosomes 6 and 20. Another known 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 inconsistent across breeds. It turned out that 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 and across-breed meta-analysis has greater power to detect such QTL than within-breed association testing. Association testing between imputed sequence variant genotypes and phenotypes of interest facilitates identifying causal mutations provided the accuracy of imputation is high. However, true causal mutations may remain undetected when the imputed sequence variant genotypes contain flaws. It is highly recommended to validate the effect of known causal variants in order to assess the ability to detect true causal mutations in association studies with imputed sequence variants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-017-4263-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5680815 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-56808152017-11-17 Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution Pausch, Hubert Emmerling, Reiner Gredler-Grandl, Birgit Fries, Ruedi Daetwyler, Hans D. Goddard, Michael E. BMC Genomics Research BACKGROUND: Genotyping and whole-genome sequencing data have been generated for hundreds of thousands of cattle. International consortia used these data to compile imputation reference panels that facilitate the imputation of sequence variant genotypes for animals that have been genotyped using dense microarrays. Association studies with imputed sequence variant genotypes allow for the characterization of quantitative trait loci (QTL) at nucleotide resolution particularly when individuals from several breeds are included in the mapping populations. RESULTS: We imputed genotypes for 28 million sequence variants in 17,229 cattle of the Braunvieh, Fleckvieh and Holstein breeds in order to compile large mapping populations that provide high power to identify QTL for milk production traits. 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 of the detected QTL were significant in more than one breed. We combined the results across breeds using meta-analysis and identified a total of 25 QTL including six that were not significant in the within-breed association studies. Two 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 QTL on chromosomes 6 and 20. Another known 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 inconsistent across breeds. It turned out that 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 and across-breed meta-analysis has greater power to detect such QTL than within-breed association testing. Association testing between imputed sequence variant genotypes and phenotypes of interest facilitates identifying causal mutations provided the accuracy of imputation is high. However, true causal mutations may remain undetected when the imputed sequence variant genotypes contain flaws. It is highly recommended to validate the effect of known causal variants in order to assess the ability to detect true causal mutations in association studies with imputed sequence variants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-017-4263-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-11-09 /pmc/articles/PMC5680815/ /pubmed/29121857 http://dx.doi.org/10.1186/s12864-017-4263-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Pausch, Hubert Emmerling, Reiner Gredler-Grandl, Birgit Fries, Ruedi Daetwyler, Hans D. Goddard, Michael E. Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution |
title | Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution |
title_full | Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution |
title_fullStr | Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution |
title_full_unstemmed | Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution |
title_short | Meta-analysis of sequence-based association studies across three cattle breeds reveals 25 QTL for fat and protein percentages in milk at nucleotide resolution |
title_sort | meta-analysis of sequence-based association studies across three cattle breeds reveals 25 qtl for fat and protein percentages in milk at nucleotide resolution |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680815/ https://www.ncbi.nlm.nih.gov/pubmed/29121857 http://dx.doi.org/10.1186/s12864-017-4263-8 |
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