A genome-wide association study of the human metabolome in a community-based cohort

Eugene P. Rhee; Jennifer E. Ho; Ming Huei Chen; Dongxiao Shen; Susan Cheng; Martin G. Larson; Anahita Ghorbani; Xu Shi; Iiro T. Helenius; Christopher J. O'Donnell; Amanda L. Souza; Amy Deik; Kerry A. Pierce; Kevin Bullock; Geoffrey A. Walford; Ramachandran S. Vasan; Jose C. Florez; Clary Clish; J. R.Joanna Yeh; Thomas J. Wang; Robert E. Gerszten

doi:10.1016/j.cmet.2013.06.013

A genome-wide association study of the human metabolome in a community-based cohort

Eugene P. Rhee, Jennifer E. Ho, Ming Huei Chen, Dongxiao Shen, Susan Cheng, Martin G. Larson, Anahita Ghorbani, Xu Shi, Iiro T. Helenius, Christopher J. O'Donnell, Amanda L. Souza, Amy Deik, Kerry A. Pierce, Kevin Bullock, Geoffrey A. Walford, Ramachandran S. Vasan, Jose C. Florez, Clary Clish, J. R.Joanna Yeh, Thomas J. WangRobert E. Gerszten

Research output: Contribution to journal › Article › peer-review

239 Scopus citations

Abstract

Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2076 participants of the Framingham Heart Study (FHS). For the majority of analytes, we find that estimated heritability explains >20% of interindividual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.

Original language	English (US)
Pages (from-to)	130-143
Number of pages	14
Journal	Cell Metabolism
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.cmet.2013.06.013
State	Published - Jul 2 2013
Externally published	Yes

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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Rhee, E. P., Ho, J. E., Chen, M. H., Shen, D., Cheng, S., Larson, M. G., Ghorbani, A., Shi, X., Helenius, I. T., O'Donnell, C. J., Souza, A. L., Deik, A., Pierce, K. A., Bullock, K., Walford, G. A., Vasan, R. S., Florez, J. C., Clish, C., Yeh, J. R. J., ... Gerszten, R. E. (2013). A genome-wide association study of the human metabolome in a community-based cohort. Cell Metabolism, 18(1), 130-143. https://doi.org/10.1016/j.cmet.2013.06.013

Rhee, EP, Ho, JE, Chen, MH, Shen, D, Cheng, S, Larson, MG, Ghorbani, A, Shi, X, Helenius, IT, O'Donnell, CJ, Souza, AL, Deik, A, Pierce, KA, Bullock, K, Walford, GA, Vasan, RS, Florez, JC, Clish, C, Yeh, JRJ, Wang, TJ & Gerszten, RE 2013, 'A genome-wide association study of the human metabolome in a community-based cohort', Cell Metabolism, vol. 18, no. 1, pp. 130-143. https://doi.org/10.1016/j.cmet.2013.06.013

@article{ddf8eff4254a462ca47f1d28fad433f6,

title = "A genome-wide association study of the human metabolome in a community-based cohort",

abstract = "Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2076 participants of the Framingham Heart Study (FHS). For the majority of analytes, we find that estimated heritability explains >20% of interindividual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.",

author = "Rhee, {Eugene P.} and Ho, {Jennifer E.} and Chen, {Ming Huei} and Dongxiao Shen and Susan Cheng and Larson, {Martin G.} and Anahita Ghorbani and Xu Shi and Helenius, {Iiro T.} and O'Donnell, {Christopher J.} and Souza, {Amanda L.} and Amy Deik and Pierce, {Kerry A.} and Kevin Bullock and Walford, {Geoffrey A.} and Vasan, {Ramachandran S.} and Florez, {Jose C.} and Clary Clish and Yeh, {J. R.Joanna} and Wang, {Thomas J.} and Gerszten, {Robert E.}",

note = "Funding Information: This work was supported by NIH contracts N01-HC-25195, R01-DK-HL-081572 (R.E.G. and T.J.W.), R01-HL-098280 (R.E.G.), R-01-HL-093328 (R.S.V.), U01-HL-107440 (R.E.G.), K23-HL-116780 (J.E.H.), K08-DK-090142 (E.P.R.), the Leducq Foundation (to R.E.G.), and the American Heart Association 12IRG9130006 (J.-R.J.Y. and I.T.H.) and 0940109N (R.E.G.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. ",

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doi = "10.1016/j.cmet.2013.06.013",

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T1 - A genome-wide association study of the human metabolome in a community-based cohort

AU - Rhee, Eugene P.

AU - Ho, Jennifer E.

AU - Chen, Ming Huei

AU - Shen, Dongxiao

AU - Cheng, Susan

AU - Larson, Martin G.

AU - Ghorbani, Anahita

AU - Shi, Xu

AU - Helenius, Iiro T.

AU - O'Donnell, Christopher J.

AU - Souza, Amanda L.

AU - Deik, Amy

AU - Pierce, Kerry A.

AU - Bullock, Kevin

AU - Walford, Geoffrey A.

AU - Vasan, Ramachandran S.

AU - Florez, Jose C.

AU - Clish, Clary

AU - Yeh, J. R.Joanna

AU - Wang, Thomas J.

AU - Gerszten, Robert E.

N1 - Funding Information: This work was supported by NIH contracts N01-HC-25195, R01-DK-HL-081572 (R.E.G. and T.J.W.), R01-HL-098280 (R.E.G.), R-01-HL-093328 (R.S.V.), U01-HL-107440 (R.E.G.), K23-HL-116780 (J.E.H.), K08-DK-090142 (E.P.R.), the Leducq Foundation (to R.E.G.), and the American Heart Association 12IRG9130006 (J.-R.J.Y. and I.T.H.) and 0940109N (R.E.G.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.

PY - 2013/7/2

Y1 - 2013/7/2

N2 - Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2076 participants of the Framingham Heart Study (FHS). For the majority of analytes, we find that estimated heritability explains >20% of interindividual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.

AB - Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2076 participants of the Framingham Heart Study (FHS). For the majority of analytes, we find that estimated heritability explains >20% of interindividual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research.

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JO - Cell Metabolism

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A genome-wide association study of the human metabolome in a community-based cohort

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