临床生物库中基于基因型的“虚拟”代谢组学确定了新的代谢产物与疾病的关联。

Minoo Bagheri, Andrei Bombin, Mingjian Shi, Venkatesh L Murthy, Ravi Shah, Jonathan D Mosley, Jane F Ferguson
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引用次数: 0

摘要

循环代谢产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。循环代谢产物个体间变异的一部分受到常见遗传变异的影响。我们评估了基于遗传学的“虚拟”代谢组学方法是否可以识别新的代谢产物与疾病的相关性。我们检测了来自BioVU DNA生物库的57735名欧洲血统和15754名非洲血统参与者的726种代谢产物(来源于OMICPRED)的多基因评分与1247种临床表型之间的关系。我们使用METSIM研究构建的遗传工具,通过孟德尔随机化(MR)探讨了显著的关系,并使用候选表型的独立GWAS验证了显著的MR关联。我们发现欧洲血统的336种代谢物和168种表型与非洲血统的107种代谢物和56种表型之间存在显著关联。在这些代谢产物-疾病对中,MR分析证实了欧洲血统中73种代谢产物和53种表型之间的关联。在独立GWAS中评估复制的22个代谢产物表型对中,有16个是显著的(假发现率p
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Genotype-based "virtual" metabolomics in a clinical biobank identifies novel metabolite-disease associations.

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 726 metabolites (derived from OMICSPRED) with 1,247 clinical phenotypes in 57,735 European ancestry and 15,754 African ancestry participants from the BioVU DNA Biobank. We probed significant relationships through Mendelian randomization (MR) using genetic instruments constructed from the METSIM Study, 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 among African ancestry. Of these metabolite-disease pairs, MR analyses confirmed associations between 73 metabolites and 53 phenotypes in European ancestry. Of 22 metabolite-phenotype pairs evaluated for replication in independent GWAS, 16 were significant (false discovery rate p<0.05). Validated findings included the metabolites bilirubin and X-21796 with cholelithiasis, phosphatidylcholine(16:0/22:5n3,18:1/20:4) and arachidonate(20:4n6) 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.

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