A Genome-wide Association Study of the Human Metabolome in a Community-Based Cohort

Abstract

SUMMARY Because metabolites are hypothesized to play key roles as markers and effectors of cardio-metabolic 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 2,076 participants of the Framingham Heart Study. For the majority of analytes, we find that estimated heritability explains >20% of inter-individual 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.

Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes

“…At both 2 and 6 months after RYGB, patients had dramatic weight loss and also significant improvements in metabolic parameters, such as glucose levels, systolic blood pressure ate, ADMA, and alanine (25). Our group and others have previously reported associations between common variants in the AGXT2 gene with circulating metabolite levels in human blood (17,20,32) and urine (17). Our data therefore extend the findings of previous studies by demonstrating that DMGV is a bona fide product of AGXT2 metabolism in humans.…”

“…However, comparison of MS/MS fragmentation of multiple authentic reported a GWAS of 217 plasma metabolite traits measured in 2,076 participants of the Framingham Heart Study (FHS). Further, and as corroborated by other published metabolite GWAS, many of the strongest associations we identified were at loci that encode transporters or enzymes with a direct biochemical relationship with the metabolite (20,21). Therefore, we hypothesized that in the context of nontargeted profiling, a genetic association with an unknown metabolite could aid in its identification by highlighting a specific enzymatic reaction.…”

“…Our data therefore extend the findings of previous studies by demonstrating that DMGV is a bona fide product of AGXT2 metabolism in humans. We have previously shown that knockdown of agxt2 in zebrafish using morpholinos modulates cholesterol and triacylglycerol metabolism (20). Quantitative trait locus analyses performed in inbred mouse strains have also suggested a potential role for Agxt2 and related pathways in liver metabolism (33), while SNPs in the AGXT2 locus have nominal association with diabetes.…”

“…Cardiometabolic traits and routine biochemical test results were available for all these subjects. Genotyping was performed on the Affymetrix GeneChip Human Mapping 500K Array SetR and 50K Human Gene Focused PanelR, with parameters and data analysis as previously described (20). Briefly, we performed a GWAS on the metabolite peak for m/z 202.1185 by imputation of 15.6 million SNPs (1000 Genomes Phase I, version 3, CEU population, March 2012 release, build 37) using a hidden Markov model that was implemented in MACH/minimac (2012-5-29 release) (https://genome.sph.umich.…”

Plasma amino acid profiles in healthy East Asian subpopulations living in Japan

“…Because these reactions are performed by various enzymes, PFAA profiles may be influenced by genetic variations in enzymes involved in AA metabolism. In fact, a prior genome‐wide association study (GWAS) of the human metabolome indicated that certain AAs are associated with genetic loci encoding either AA transporters or enzymes involved in serine (Ser) biosynthesis (Rhee et al, 2013). …”