Journal
METABOLITES
Volume 12, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/metabo12060496
Keywords
medication; drug metabolites; population studies; non-targeted metabolomics; genome-wide association studies; acetaminophen metabolism; pharmacogenomics; 3-methoxyacetaminophen
Categories
Funding
- Biomedical Research Program at Weill Cornell Medicine in Qatar - Qatar Foundation
- Qatar National Research Fund (QNRF) [NPRP11C-0115-180010]
- Qatar Foundation
Ask authors/readers for more resources
The study proposes the use of metabolite ratios as GWAS phenotypes to increase the power of detecting genetic associations. A GWAS with 520 individuals identified genetic variations related to acetaminophen metabolism, and confirmed the chemical structure of one of its products experimentally.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available