Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Jul 2;18(1):130-43.
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  1 , 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
Affiliations

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

Eugene P Rhee et al. Cell Metab. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. see also Figure S1 and Table S1. Genetic architecture of the human plasma metabolome
(A) The percent inter-individual variation for positively charged, polar metabolites explained by clinical (black) and genetic factors: top SNP (green), second top SNP (red), other genetic factors (grey). Clinical factors include age, sex, systolic blood pressure, anti-hypertensive medication use, diabetes mellitus, smoking status, body-mass index, and prevalent cardiovascular disease. (B) Data summarized for non-essential and essential amino acids.
Figure 2
Figure 2. see also Figures S2 and S3. Thirty-one genome-wide significant loci associated with metabolites in FHS
Loci with significant metabolite associations in FHS are depicted within the black circle. Overlap with prior studies (dotted circles) is indicated for 8 loci. Prior studies found an association between common variants at *AGXT2 and urinary levels of β-aminoisobutyric acid, †GCKR and the alanine/glutamine ratio, and ‡SLC16A10 and the tyrosine/isoleucine and alanine/tyrosine ratios.
Figure 3
Figure 3. Metabolite profiling demonstrates distinct patterns of TAG associations for select loci
For the 46 triacylglycerols (TAGs) monitored by our platform, the beta coefficient (left y-axis) and P-value (right y-axis) of association are shown for the top variant at (A) GCKR, (B) FADS1-3, (C) APOA1/C3/A4/A5, and (D) rs6593086.
Figure 4
Figure 4. Phosphatidylcholine associations for the GCKR and FADS1-3 loci
For the 18 phosphatidylcholines (PCs) monitored by our platform, the beta coefficient (left y-axis) and P-value (right y-axis) of association are shown for the top variant at (A) GCKR and (B) FADS1-3.
Figure 5
Figure 5. see also Figures S4 and S5 and Table S4. AGXT2 modulates lipid homeostasis in zebrafish
(A) Zebrafish embryos were injected with 2nL of a 400uM solution of a splice blocking agxt2 morpholino oligonucleotide (MO) or control MO. At 48 hpf, agxt2 MO injection resulted in morphants with both normal phenotype (upper right panel, “AGXT2 I”) and morphants with defective yolk sac extension and pericardial edema (lower left panel, “AGXT2 II”). (B) RT-PCR of agxt2 mRNA for control, AGXT2 I and AGXT2 II morphants at 48 hpf; the 300 nucleotide fragment is the WT agxt2 transcript and the 109 nucleotide fragment is the knocked-down (KD) agxt2 transcript. The relative extent of WT agxt2 expression, normalized to rpl13-α, was estimated from band intensities; data are presented as mean ± SD, *P<0.05 for comparison to control. (C) β-aminoisobutyric acid levels in control, AGXT2 I and AGXT2 II morphants at 48 hpf; data are presented as mean ± SD, *P<0.05 for comparison to control. (D) CE and (E) TAG levels for control, AGXT2 I and AGXT II larvae at 5 dpf; data are presented as mean ± SD, *P<0.05 for comparison to control, #P<0.05 for comparison to AGXT2 I. (F) For TAGs (solid circles) and CEs (hollow circles), plot of each metabolite’s association with rs37370 (AGXT2) in FHS on the x-axis versus the percent difference for each metabolite in AGXT I versus control zebrafish on the y-axis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abhary S, Burdon KP, Kuot A, Javadiyan S, Whiting MJ, Kasmeridis N, Petrovsky N, Craig JE. Sequence variation in DDAH1 and DDAH2 genes is strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes. PLoS One. 2010;5:e9462. - PMC - PubMed
    1. Adamski J. Genome-wide association studies with metabolomics. Genome Med. 2012;4:34. - PMC - PubMed
    1. Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 1998;62:1198–1211. - PMC - PubMed
    1. Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M, Gloyn AL. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet. 2009;18:4081–4088. - PMC - PubMed
    1. Bellenguez C, Bevan S, Gschwendtner A, Spencer CC, Burgess AI, Pirinen M, Jackson CA, Traylor M, Strange A, Su Z, et al. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat. Genet. 2012;44:328–333. - PMC - PubMed

Publication types