Bagheri Minoo, Bombin Andrei, Shi Mingjian, Murthy Venkatesh L, Shah Ravi, Mosley Jonathan D, Ferguson Jane F
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, United States.
Front Genet. 2024 May 15;15:1392622. doi: 10.3389/fgene.2024.1392622. eCollection 2024.
Circulating metabolites act as biomarkers of dysregulated metabolism and may inform disease pathophysiology. A portion of the inter-individual variability in circulating metabolites is influenced by common genetic variation. We evaluated whether a genetics-based "virtual" metabolomics approach can identify novel metabolite-disease associations. We examined the association between polygenic scores for 724 metabolites with 1,247 clinical phenotypes in the BioVU DNA biobank, comprising 57,735 European ancestry and 15,754 African ancestry participants. We applied Mendelian randomization (MR) to probe significant relationships and validated significant MR associations using independent GWAS of candidate phenotypes. We found significant associations between 336 metabolites and 168 phenotypes in European ancestry and 107 metabolites and 56 phenotypes in African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolitephenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p < 0.05). These included associations between bilirubin and X-21796 with cholelithiasis, phosphatidylcholine (16:0/22:5n3,18:1/20:4) and arachidonate with inflammatory bowel disease and Crohn's disease, and campesterol with coronary artery disease and myocardial infarction. These associations may represent biomarkers or potentially targetable mediators of disease risk.
循环代谢物作为代谢失调的生物标志物，可能为疾病病理生理学提供信息。循环代谢物个体间差异的一部分受常见基因变异影响。我们评估了基于遗传学的“虚拟”代谢组学方法是否能识别新的代谢物与疾病的关联。我们在BioVU DNA生物样本库中研究了724种代谢物的多基因评分与1247种临床表型之间的关联，该样本库包括57735名欧洲血统参与者和15754名非洲血统参与者。我们应用孟德尔随机化（MR）来探究显著关系，并使用候选表型的独立全基因组关联研究（GWAS）验证显著的MR关联。我们发现欧洲血统中有336种代谢物与168种表型存在显著关联，非洲血统中有107种代谢物与56种表型存在显著关联。在这些代谢物与疾病的配对中，MR分析证实欧洲血统中有73种代谢物与53种表型存在关联。在独立GWAS中评估的22对代谢物与表型配对中，16对具有显著性（错误发现率p<0.05）。这些关联包括胆红素和X-21796与胆结石、磷脂酰胆碱（16:0/22:5n3,18:1/20:4）和花生四烯酸与炎症性肠病和克罗恩病，以及菜油甾醇与冠状动脉疾病和心肌梗死之间的关联。这些关联可能代表疾病风险的生物标志物或潜在的可靶向调节因子。
