Multi-population GWAS and enrichment analyses reveal novel genomic regions and promising candidate genes underlying bovine milk fatty acid composition

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Abstract

Background

The power of genome-wide association studies (GWAS) is often limited by the sample size available for the analysis. Milk fatty acid (FA) traits are scarcely recorded due to expensive and time-consuming analytical techniques. Combining multi-population datasets can enhance the power of GWAS enabling detection of genomic region explaining medium to low proportions of the genetic variation. GWAS often detect broader genomic regions containing several positional candidate genes making it difficult to untangle the causative candidates. Post-GWAS analyses with data on pathways, ontology and tissue-specific gene expression status might allow prioritization among positional candidate genes.

Results

Multi-population GWAS for 16 FA traits quantified using gas chromatography (GC) in sample populations of the Chinese, Danish and Dutch Holstein with high-density (HD) genotypes detects 56 genomic regions significantly associated to at least one of the studied FAs; some of which have not been previously reported. Pathways and gene ontology (GO) analyses suggest promising candidate genes on the novel regions including OSBPL6 and AGPS on Bos taurus autosome (BTA) 2, PRLH on BTA 3, SLC51B on BTA 10, ABCG5/8 on BTA 11 and ALG5 on BTA 12. Novel genes in previously known regions, such as FABP4 on BTA 14, APOA1/5/7 on BTA 15 and MGST2 on BTA 17, are also linked to important FA metabolic processes.

Conclusion

Integration of multi-population GWAS and enrichment analyses enabled detection of several novel genomic regions, explaining relatively smaller fractions of the genetic variation, and revealed highly likely candidate genes underlying the effects. Detection of such regions and candidate genes will be crucial in understanding the complex genetic control of FA metabolism. The findings can also be used to augment genomic prediction models with regions collectively capturing most of the genetic variation in the milk FA traits.

Electronic supplementary material

The online version of this article (10.1186/s12864-019-5573-9) contains supplementary material, which is available to authorized users.

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Most cited references 65

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Positional candidate cloning of a QTL in dairy cattle: identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition.

Bernard Grisart, Wouter Coppieters, Frédéric Farnir … (2002)

We recently mapped a quantitative trait locus (QTL) with a major effect on milk composition--particularly fat content--to the centromeric end of bovine chromosome 14. We subsequently exploited linkage disequilibrium to refine the map position of this QTL to a 3-cM chromosome interval bounded by microsatellite markers BULGE13 and BULGE09. We herein report the positional candidate cloning of this QTL, involving (1) the construction of a BAC contig spanning the corresponding marker interval, (2) the demonstration that a very strong candidate gene, acylCoA:diacylglycerol acyltransferase (DGAT1), maps to that contig, and (3) the identification of a nonconservative K232A substitution in the DGAT1 gene with a major effect on milk fat content and other milk characteristics.

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miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling.

Alberto Davalos, Leigh Goedeke, Peter Smibert … (2011)

Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs hsa-miR-33a and hsa-miR-33b are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.

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Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.

K Berge, H. Tian, G. A. Graf … (2000)

In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.

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Author and article information

Contributors

G. Gebreyesus:

ORCID: http://orcid.org/0000-0003-4757-3060

grum.gebreyesus@mbg.au.dk

A. J. Buitenhuis: bart.buitenhuis@mbg.au.dk

N. A. Poulsen: nina.poulsen@food.au.dk

M. H. P. W. Visker: marleen.visker@wur.nl

Q. Zhang: qzhang@cau.edu.cn

H. J. F. van Valenberg: hein.vanvalenberg@wur.nl

D. Sun: sundx@cau.edu.cn

H. Bovenhuis: henk.bovenhuis@wur.nl

Journal

Journal ID (nlm-ta): BMC Genomics

Journal ID (iso-abbrev): BMC Genomics

Title: BMC Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2164

Publication date (Electronic): 6 March 2019

Publication date PMC-release: 6 March 2019

Publication date Collection: 2019

Volume: 20

Electronic Location Identifier: 178

Affiliations

[1 ]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Center for Quantitative Genetics and Genomics, Department of Molecular Biology and Genetics, , Aarhus University, ; Blichers Allé 20, P.O. Box 50, DK-8830 Tjele, Denmark

[2 ]ISNI 0000 0001 0791 5666, GRID grid.4818.5, Animal Breeding and Genomics, , Wageningen University and Research, ; P.O. Box 338, 6700 AH Wageningen, the Netherlands

[3 ]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Department of Food Science, , Aarhus University, ; Blichers Allé 20, P.O. Box 50, DK-8830 Tjele, Denmark

[4 ]ISNI 0000 0004 0530 8290, GRID grid.22935.3f, Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture of China, National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, , China Agricultural University, ; Beijing, 100193 China

[5 ]ISNI 0000 0001 0791 5666, GRID grid.4818.5, Dairy Science and Technology Group, , Wageningen University and Research, ; P.O. Box 17, 6700 AA Wageningen, the Netherlands

Author information

G. Gebreyesus http://orcid.org/0000-0003-4757-3060

Article

Publisher ID: 5573

DOI: 10.1186/s12864-019-5573-9

PMC ID: 6404302

PubMed ID: 30841852

SO-VID: b21cf512-2ad7-4c69-84ad-2f143b35a3a3

License:

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.

History

Date received : 8 September 2018

Date accepted : 28 February 2019

Funding

Funded by: European commision

Funded by: FundRef http://dx.doi.org/10.13039/100012774, Innovationsfonden;

Award ID: 0603-00519B

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: milk fatty acids,multi-population gwas,candidate genes,pathway analysis

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ScienceOpen disciplines: Genetics

Keywords: milk fatty acids, multi-population gwas, candidate genes, pathway analysis

Multi-population GWAS and enrichment analyses reveal novel genomic regions and promising candidate genes underlying bovine milk fatty acid composition

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Most cited references 65

Positional candidate cloning of a QTL in dairy cattle: identification of a missense mutation in the bovine DGAT1 gene with major effect on milk yield and composition.

miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling.

Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.

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