Genetic regulation of mouse liver metabolite levels

Molecular Systems Biology

Anatole Ghazalpour²  Brian J Bennett²  Diana Shih²  Nam Che²  Luz Orozco³  Calvin Pan⁵  Raffi Hagopian²  Aiqing He¹  Paul Kayne¹  Wen-pin Yang¹  Todd Kirchgessner⁴ 

[1] Department of Applied Genomics, Bristol-Myers Squibb, Princeton, NJ, USA;Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA;Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA, USA;Department of Atherosclerosis Drug Discovery, Bristol-Myers Squibb, Princeton, NJ, USA;Department of Human Genetics, UCLA, Los Angeles, CA, USA

关键词: genome‐wide association;    local eQTL;    metabolome;    QTL;    transcriptome;   

DOI  :  10.15252/msb.20135004

来源: Wiley

【 摘 要 】

Abstract

We profiled and analyzed 283 metabolites representing eight major classes of molecules including Lipids, Carbohydrates, Amino Acids, Peptides, Xenobiotics, Vitamins and Cofactors, Energy Metabolism, and Nucleotides in mouse liver of 104 inbred and recombinant inbred strains. We find that metabolites exhibit a wide range of variation, as has been previously observed with metabolites in blood serum. Using genome-wide association analysis, we mapped 40% of the quantified metabolites to at least one locus in the genome and for 75% of the loci mapped we identified at least one candidate gene by local expression QTL analysis of the transcripts. Moreover, we validated 2 of 3 of the significant loci examined by adenoviral overexpression of the genes in mice. In our GWAS results, we find that at significant loci the peak markers explained on average between 20 and 40% of variation in the metabolites. Moreover, 39% of loci found to be regulating liver metabolites in mice were also found in human GWAS results for serum metabolites, providing support for similarity in genetic regulation of metabolites between mice and human. We also integrated the metabolomic data with transcriptomic and clinical phenotypic data to evaluate the extent of co-variation across various biological scales.

Synopsis

Mouse liver metabolites were quantified by mass spectrometry and mapped by genome-wide association. Genetic factors were shown to contribute substantially to metabolite levels and adenoviral overexpression validated several of the identified loci.

• Liver metabolites exhibit a wide range of variation, indicating strong genetic influences.
• Approximately 40% of metabolites are estimated to be regulated by genetic factors.
• A significant overlap was observed between genetic factors regulating mouse liver metabolites and genetic factors regulating human serum metabolites.
• Metabolite levels correlated significantly both with each other and with other phenotypes such as transcript levels and physiological traits.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.