Although Alzheimer's disease (AD) is highly heritable, genetic variants are known to be associated with AD only explain a small proportion of its heritability. Genetic factors may only convey disease risk in individuals with certain environmental exposures, suggesting that a multiomics approach could reveal underlying mechanisms contributing to complex traits, such as AD. We developed an integrated network to investigate relationships between metabolomics, genomics, and AD risk factors using Wisconsin Registry for Alzheimer's Prevention participants. Analyses included 1,111 non-Hispanic Caucasian participants with whole blood expression for 11,376 genes (imputed from dense genome-wide genotyping), 1,097 fasting plasma metabolites, and 17 AD risk factors. A subset of 155 individuals also had 364 fastings cerebral spinal fluid (CSF) metabolites. After adjusting each of these 12,854 variables for potential confounders, we developed an undirected graphical network, representing all significant pairwise correlations upon adjusting for multiple testing. There were many instances of genes being indirectly linked to AD risk factors through metabolites, suggesting that genes may influence AD risk through particular metabolites. Follow-up analyses suggested that glycine mediates the relationship between carbamoyl-phosphate synthase 1 and measures of cardiovascular and diabetes risk, including body mass index, waist-hip ratio, inflammation, and insulin resistance. Further, 38 CSF metabolites explained more than 60% of the variance of CSF levels of tau, a detrimental protein that accumulates in the brain of AD patients and is necessary for its diagnosis. These results further our understanding of underlying mechanisms contributing to AD risk while demonstrating the utility of generating and integrating multiple omics data types.

中文翻译：

---

对1,111名队列参与者的基因组学，纵向代谢组学和阿尔茨海默氏症危险因素的综合分析。

尽管阿尔茨海默氏病（AD）具有高度的遗传性，但已知遗传变异与AD相关，仅能解释其遗传性的一小部分。遗传因素只能在具有一定环境暴露的个体中传达疾病风险，这表明多组学方法可以揭示导致复杂性状如AD的潜在机制。我们使用威斯康星州注册机构为阿尔茨海默氏症预防参与者开发了一个集成网络，以研究代谢组学，基因组学和AD危险因素之间的关系。分析包括1,111名非西班牙裔白种人参与者，他们有11,376个基因（从密集的全基因组基因型推算），全血表达，1,097个空腹血浆代谢物和17个AD危险因素。155个个体的子集还具有364个禁食的脑脊髓液（CSF）代谢产物。在为潜在的混杂因素调整了这12,854个变量中的每个变量之后，我们开发了无向的图形网络，表示针对多个测试进行调整后所有显着的成对相关性。基因通过代谢产物与AD危险因素间接相关的例子很多，这表明基因可能通过特定代谢产物影响AD风险。后续分析表明，甘氨酸介导氨基甲酰磷酸合酶1与心血管疾病和糖尿病风险的度量之间的关系，包括体重指数，腰臀比，炎症和胰岛素抵抗。此外，有38种CSF代谢物解释了tau CSF水平变异的60％以上，一种有害蛋白质，会积聚在AD患者的大脑中，是其诊断所必需的。这些结果使我们进一步了解了导致AD风险的潜在机制，同时展示了生成和集成多种组学数据类型的实用性。