Ratios of Acetaminophen Metabolites Identify New Loci of Pharmacogenetic Relevance in a Genome-Wide Association Study

Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power an...

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Published inMetabolites Vol. 12; no. 6; p. 496
Main Authors Thareja, Gaurav, Evans, Anne M., Wood, Spencer D., Stephan, Nisha, Zaghlool, Shaza, Halama, Anna, Kastenmüller, Gabi, Belkadi, Aziz, Albagha, Omar M. E., Suhre, Karsten
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 30.05.2022
MDPI
Subjects
Acetaminophen
acetaminophen metabolism
Analgesics
drug metabolites
Enzymes
Gene expression
Genetic diversity
Genome-wide association studies
Genomes
medication
Metabolism
Metabolites
Metabolomics
Methylation
non-targeted metabolomics
Phenotypes
Population studies
Xenobiotics
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Summary:Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power and higher uncertainty in their quantification. Here we propose ratios between related drug metabolites as GWAS phenotypes that can drastically increase power to detect genetic associations between pairs of biochemically related molecules. As a proof-of-concept we conducted a GWAS with 520 individuals from the Qatar Biobank for who at least five of the nine available acetaminophen metabolites have been detected. We identified compelling evidence for genetic variance in acetaminophen glucuronidation and methylation by UGT2A15 and COMT, respectively. Based on the metabolite ratio association profiles of these two loci we hypothesized the chemical structure of one of their products or substrates as being 3-methoxyacetaminophen, which we then confirmed experimentally. Taken together, our study suggests a novel approach to analyze metabolites with a high degree of missingness in a GWAS setting with ratios, and it also demonstrates how pharmacological pathways can be mapped out using non-targeted metabolomics measurements in large population-based studies.
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A list of consortium authors and affiliations is provided as Supplementary Materials.
ISSN:2218-1989
2218-1989
DOI:10.3390/metabo12060496