PDF(Pubmed)
Abstract：
Dysregulation of fatty acid metabolites can play a crucial role in the progression of complex diseases, such as cardiovascular disease, digestive diseases, and metabolic diseases. Metabolites can have either protective or risk effects on a disease; however, the details of such associations remain contentious. In this study, we demonstrate an integrative PheWAS approach to establish high confidence, causally suggestive of metabolite-disease associations for three fatty acid metabolites, namely, omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, for 1,254 disease endpoints. Metabolite-disease associations were established if there was a concordant direction of effect and significance for metabolite level and genetic risk score for the metabolite. There was enrichment for metabolite associations with diseases of the respiratory system for omega-3 fatty acids, diseases of the circulatory system and endocrine system for omega-6 fatty acids, and diseases of the digestive system for docosahexaenoic acid. Upon performing Mendelian randomization on a subset of the outcomes, we identified 3, 6, and 15 significant diseases associated with omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, respectively. We then demonstrate a class of prevalence-risk relationships indicative of (de)canalization of disease under high and low fatty acid metabolite levels. Finally, we show that the interaction between the metabolites and obesity demonstrates that the degree of protection afforded by fatty acid metabolites is strongly modulated by underlying metabolic health. This study evaluated the disease architectures of three polyunsaturated fatty acids (PUFAs), which were validated by several PheWAS modes of support. Our results not only highlight specific diseases associated with each metabolite but also disease group enrichments. In addition, we demonstrate an integrative PheWAS methodology that can be applied to other components of the human metabolome or other traits of interest. The results of this study can be used as an atlas to cross-compare genetic with non-genetic disease associations for the three PUFAs investigated. The findings can be explored through our R shiny app at https://pufa.biosci.gatech.edu.
摘要：
脂肪酸代谢产物的失调在复杂疾病的进展中起着至关重要的作用。比如心血管疾病，消化系统疾病,和代谢性疾病。代谢物可能对疾病有保护作用或风险作用；然而，这种协会的细节仍然有争议。在这项研究中,我们展示了一种综合的Phewas方法来建立高置信度，因果关系提示三种脂肪酸代谢物的代谢物-疾病关联，即,omega-3脂肪酸，omega-6脂肪酸，和二十二碳六烯酸,1,254个疾病终点。如果代谢物水平和代谢物的遗传风险评分的作用和意义一致，则建立了代谢物-疾病关联。代谢产物与呼吸系统疾病的结合富集了omega-3脂肪酸，疾病的循环系统和内分泌系统的ω-6脂肪酸，和消化系统疾病的二十二碳六烯酸。在对结果的子集进行孟德尔随机化后，我们确定了3、6和15种与omega-3脂肪酸相关的重大疾病，omega-6脂肪酸，和二十二碳六烯酸,分别。然后，我们证明了一类患病率-风险关系，表明在高和低脂肪酸代谢物水平下疾病的（去）规范化。最后,我们表明代谢产物与肥胖之间的相互作用表明，脂肪酸代谢产物提供的保护程度受到潜在代谢健康的强烈调节。这项研究评估了三种多不饱和脂肪酸(PUFA)的疾病结构，通过几种Phewas支持模式进行了验证。我们的结果不仅突出了与每种代谢物相关的特定疾病，而且还突出了疾病组的富集。此外,我们展示了一种可应用于人类代谢组其他组分或其他目标性状的综合PheWAS方法。这项研究的结果可以用作地图集，以交叉比较所研究的三种PUFA的遗传与非遗传疾病关联。这些发现可以通过我们的R闪亮应用程序在https://pufa进行探索。Biosci.gatech.edu.
