Thareja Gaurav, Evans Anne M, Wood Spencer D, Stephan Nisha, Zaghlool Shaza, Halama Anna, Kastenmüller Gabi, Belkadi Aziz, Albagha Omar M E, Suhre Karsten
Bioinformatics Core, Weill Cornell Medicine-Qatar, Education City, Doha P.O. Box 24144, Qatar.
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA.
Metabolites. 2022 May 30;12(6):496. doi: 10.3390/metabo12060496.
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.
全基因组关联研究（GWAS）结合非靶向代谢组学已经确定了许多具有生物医学意义的基因位点。然而，具有高度缺失值的代谢物，如药物代谢物和外源性物质，由于缺乏统计效力以及其定量存在较高不确定性，往往被排除在这类研究之外。在此，我们提出将相关药物代谢物之间的比率作为GWAS表型，这可以显著提高检测生化相关分子对之间遗传关联的效力。作为概念验证，我们对卡塔尔生物样本库中的520名个体进行了GWAS，这些个体中至少检测到了九种可用对乙酰氨基酚代谢物中的五种。我们分别通过UGT2A15和COMT鉴定出了对乙酰氨基酚葡萄糖醛酸化和甲基化存在遗传变异的有力证据。基于这两个基因座的代谢物比率关联图谱，我们推测它们其中一种产物或底物的化学结构为3 - 甲氧基对乙酰氨基酚，随后我们通过实验证实了这一点。综上所述，我们的研究提出了一种在GWAS环境中利用比率分析高度缺失代谢物的新方法，同时也展示了如何在基于大群体的研究中使用非靶向代谢组学测量来绘制药理学途径。
