Untargeted Metabolome- and Transcriptome-Wide Association Study Suggests Causal Genes Modulating Metabolite Concentrations in Urine.

Details

Serval ID
serval:BIB_83A8DE848FD3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Untargeted Metabolome- and Transcriptome-Wide Association Study Suggests Causal Genes Modulating Metabolite Concentrations in Urine.
Journal
Journal of proteome research
Author(s)
Sönmez Flitman R., Khalili B., Kutalik Z., Rueedi R., Brümmer A., Bergmann S.
ISSN
1535-3907 (Electronic)
ISSN-L
1535-3893
Publication state
Published
Issued date
05/11/2021
Peer-reviewed
Oui
Volume
20
Number
11
Pages
5103-5114
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Gene products can affect the concentrations of small molecules (aka "metabolites"), and conversely, some metabolites can modulate the concentrations of gene transcripts. While many specific instances of this interplay have been revealed, a global approach to systematically uncover human gene-metabolite interactions is still lacking. We performed a metabolome- and transcriptome-wide association study to identify genes influencing the human metabolome using untargeted metabolome features, extracted from <sup>1</sup> H nuclear magnetic resonance spectroscopy (NMR) of urine samples, and gene expression levels, quantified from RNA-Seq of lymphoblastoid cell lines (LCL) from 555 healthy individuals. We identified 20 study-wide significant associations corresponding to 15 genes, of which 5 associations (with 2 genes) were confirmed with follow-up NMR data. Using metabomatching, we identified the metabolites corresponding to metabolome features associated with the genes, namely, N-acetylated compounds with ALMS1 and trimethylamine (TMA) with HPS1. Finally, Mendelian randomization analysis supported a potential causal link between the expression of genes in both the ALMS1- and HPS1-loci and their associated metabolite concentrations. In the case of HPS1, we additionally observed that TMA concentration likely exhibits a reverse causal effect on HPS1 expression levels, indicating a negative feedback loop. Our study highlights how the integration of metabolomics, gene expression, and genetic data can pinpoint causal genes modulating metabolite concentrations.
Keywords
Alms1, Hps1, N-acetylated compounds, Nat8, Pyroxd2, genome-wide association study, metabolomics, transcriptomics, trimethylamine, ALMS1, HPS1, NAT8, PYROXD2
Pubmed
Open Access
Yes
Create date
03/11/2021 14:32
Last modification date
12/11/2021 7:40
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