Human metabolic individuality in biomedical and pharmaceutical research

摘要

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.%遗传倾向与环境因素之司的相互作用是复杂疾病发病机理的关键。用来了解这种关系的一个很有希望的方法，将全基因组关联研究(GWAS)与对作为功能性中间体表现型的血液代谢物的分析综合在了一起。这种方法的淄力由一个大型合作研究项目得到了展示，该项目综合了来自德国KORA F4和英国TwinsUK两个人群的研究数据。