ArticlePLoS genetics2012
Mining the unknown: a systems approach to metabolite identification combining genetic and metabolic information.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 136 papers, 3 of them syntheses that pooled it.
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Who cites it
136 citing papers in PubMed, 3 syntheses or guidelines pooled it, 210 citations in OpenAlex.
- Use of Mendelian Randomization to Unveil Metabolic Markers inJournal of Korean medical science · 2026Pooled it
- Causal relationships of metabolites with allergic diseases: a trans-ethnic Mendelian randomization study.Respiratory research · 2024Pooled it
- Potential Causal Association between Plasma Metabolites, Immunophenotypes, and Female Reproductive Disorders: A Two-Sample Mendelian Randomization Analysis.Biomolecules · 2024Pooled it
- Association of Physical Activity With Bioactive Lipids and Cardiovascular Events.Circulation research · 2022Trial
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- Lipid metabolic networks, Mediterranean diet and cardiovascular disease in the PREDIMED trial.International journal of epidemiology · 2018Trial
- Gut microbiota and plasma metabolites associated with diabetes in women with, or at high risk for, HIV infection.EBioMedicine · 2018Trial
- Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes.The Journal of clinical investigation · 2017Trial
- BMI-Dependent Correlations of Sex Hormone Genes with Simple Endometrial Hyperplasia.Life (Basel, Switzerland) · 2026Article
- The non-linear and linear effects of CYP2C19 metaboliser status on DNA methylation: a methylome-wide association study.Clinical epigenetics · 2026Article
- Integrative serum metabolite prioritization and functional screening identify N-acetyl-L-glutamine as a protective candidate in premature ovarian insufficiency.Frontiers in genetics · 2026Article
- Application of Mendelian randomization to explore metabolic pathways in colorectal cancer.Annals of medicine and surgery (2012) · 2025Article
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- N-lactoyl amino acids are potential biomarkers for insulin resistance and diabetic complications.Diabetes, obesity & metabolism · 2025Article
- Metabolomic signatures of cognitive function in a type 2 Diabetes-Enriched cohort.Scientific reports · 2025Article
- Effect of the plasma metabolites, biomarkers, and inflammatory proteins on urolithiasis: insights from Mendelian randomization and mediation analysis.Urolithiasis · 2025Article
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- Merging metabolomics and genomics provides a catalog of genetic factors that influence molecular phenotypes in pigs linking relevant metabolic pathways.Genetics, selection, evolution : GSE · 2025Article
- New therapeutic targets for endometriosis predicted through mendelian randomization analysis and case-control trials.Frontiers in genetics · 2025Article
- Article
76 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent genome-wide association studies (GWAS) with metabolomics data linked genetic variation in the human genome to differences in individual metabolite levels. A strong relevance of this metabolic individuality for biomedical and pharmaceutical research has been reported. However, a considerable amount of the molecules currently quantified by modern metabolomics techniques are chemically unidentified. The identification of these "unknown metabolites" is still a demanding and intricate task, limiting their usability as functional markers of metabolic processes. As a consequence, previous GWAS largely ignored unknown metabolites as metabolic traits for the analysis. Here we present a systems-level approach that combines genome-wide association analysis and Gaussian graphical modeling with metabolomics to predict the identity of the unknown metabolites. We apply our method to original data of 517 metabolic traits, of which 225 are unknowns, and genotyping information on 655,658 genetic variants, measured in 1,768 human blood samples. We report previously undescribed genotype-metabotype associations for six distinct gene loci (SLC22A2, COMT, CYP3A5, CYP2C18, GBA3, UGT3A1) and one locus not related to any known gene (rs12413935). Overlaying the inferred genetic associations, metabolic networks, and knowledge-based pathway information, we derive testable hypotheses on the biochemical identities of 106 unknown metabolites. As a proof of principle, we experimentally confirm nine concrete predictions. We demonstrate the benefit of our method for the functional interpretation of previous metabolomics biomarker studies on liver detoxification, hypertension, and insulin resistance. Our approach is generic in nature and can be directly transferred to metabolomics data from different experimental platforms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.