Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Faculty of Biology, Ludwig-Maximilians-Universität, Planegg-Martinsried, Germany.
Nature. 2011 Aug 31;477(7362):54-60. doi: 10.1038/nature10354.
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
全基因组关联研究（GWAS）已经确定了许多复杂疾病的风险位点，但效应大小通常较小，并且有关潜在生物学过程的信息通常缺乏。将代谢特征作为功能中间产物的关联可以克服这些问题，并有可能为个体化治疗提供信息。在这里，我们使用靶向代谢组学的 GWAS 报告了对基因型依赖性代谢表型的全面分析。我们确定了 37 个与血液代谢物浓度相关的遗传位点，其中 25 个显示出 GWAS 中异常高的效应大小，并解释了每个等位基因拷贝代谢物水平差异的 10-60%。我们的关联为以前研究中报道的许多与疾病相关的关联提供了新的功能见解，包括心血管和肾脏疾病、2 型糖尿病、癌症、痛风、静脉血栓栓塞和克罗恩病。该研究推进了我们对人类代谢个体遗传基础的认识，并为生物医学和药物研究产生了许多新的假设。
