An exome array study of the plasma metabolome.
An exome array study of the plasma metabolome.
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DOI：
10.1038/ncomms12360
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发表时间：
2016-07-25
影响因子：
16.6
通讯作者：
Gerszten RE
中科院分区：
文献类型：
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作者：
Rhee EP;Yang Q;Yu B;Liu X;Cheng S;Deik A;Pierce KA;Bullock K;Ho JE;Levy D;Florez JC;Kathiresan S;Larson MG;Vasan RS;Clish CB;Wang TJ;Boerwinkle E;O'Donnell CJ;Gerszten RE
对罕见变异的研究可能会增强我们对代谢组遗传决定因素的理解。在这里，我们分析了217种血浆代谢物与Illumina HumanExome Beadchip上外显子组变体之间的关联，其中2，076名参与者参与了心脏病研究，1，528名参与者参与了社区动脉粥样硬化风险研究。我们使用单变异分析确定了GMPS和黄嘌呤核苷之间的关联，使用基于基因的检验确定了HAL和组氨酸、PAH和苯丙氨酸、UPB 1和脲基丙酸之间的关联（荟萃分析中P<5 × 10−8），突出了可能导致先天性代谢缺陷的新编码变异。此外，我们还展示了如何检查等位基因频率谱中的变异，突出显示选定基因座的独立关联信号，并生成代谢物遗传性的更综合的视图。这些研究建立在先前的代谢组学全基因组关联研究的基础上，以提供血浆代谢组的遗传结构的更完整的图片。 几个GWAS已经确定了许多与血液代谢物相关的常见变异。在这里，作者使用外显子组阵列来识别影响人类代谢的低频，潜在的功能变体。
The study of rare variants may enhance our understanding of the genetic determinants of the metabolome. Here, we analyze the association between 217 plasma metabolites and exome variants on the Illumina HumanExome Beadchip in 2,076 participants in the Framingham Heart Study, with replication in 1,528 participants of the Atherosclerosis Risk in Communities Study. We identify an association between GMPS and xanthosine using single variant analysis and associations between HAL and histidine, PAH and phenylalanine, and UPB1 and ureidopropionate using gene-based tests (P<5 × 10−8 in meta-analysis), highlighting novel coding variants that may underlie inborn errors of metabolism. Further, we show how an examination of variants across the spectrum of allele frequency highlights independent association signals at select loci and generates a more integrated view of metabolite heritability. These studies build on prior metabolomics genome wide association studies to provide a more complete picture of the genetic architecture of the plasma metabolome. Several GWAS have identified many common variants associated with blood metabolites. Here, the authors use an exome array to identify low frequency, potentially functional variants that impact human metabolism.