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Association between Human Blood Metabolome and the Risk of Alzheimer's Disease

代谢组 优势比 置信区间 内科学 医学 谷氨酰胺 代谢物 痴呆 疾病 全基因组关联研究 生理学 生物 遗传学 基因型 单核苷酸多态性 基因 氨基酸
作者
Lulu Sun,Daoxia Guo,Yiming Jia,Mengyao Shi,Pinni Yang,Yu Wang,Fanghua Liu,Guo‐Chong Chen,Yonghong Zhang,Zhengbao Zhu
出处
期刊:Annals of Neurology [Wiley]
卷期号:92 (5): 756-767 被引量:28
标识
DOI:10.1002/ana.26464
摘要

Alzheimer's disease (AD) is the most common degenerative neurological disorder with limited therapeutic options. Therefore, it is particularly important to explore the potential biomarkers implicated in the occurrence and progression of AD prior to clinical testing.We selected 119 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with 147,827 European participants. Summary data about AD were obtained from a GWAS meta-analysis with 63,926 European individuals from the International Genomics of Alzheimer's Project. MR analyses were performed to assess the associations of blood metabolites with AD, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions.Four metabolites were identified as causal mediators for AD, including epiandrosterone sulfate (odds ratio [OR] per SD increase: 0.60; 95% confidence interval [CI]: 0.51-0.71; p = 6.14 × 10-9 ), 5alpha-androstan-3beta-17beta-diol disulfate (OR per SD increase: 0.69; 95% CI: 0.57-0.84; p = 1.98 × 10-4 ), sphingomyelin (OR per SD increase: 2.53; 95% CI: 1.78-3.59; p = 2.10 × 10-7 ), and glutamine (OR per SD increase: 0.83; 95% CI: 0.77-0.89; p = 2.09 × 10-6 ). Phenome-wide MR analysis showed that epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate and sphingomyelin mediated the risk of multiple diseases, and glutamine had beneficial effects on the risk of 4 diseases.Genetically predicted increased epiandrosterone sulfate, 5alpha-androstan-3beta-17beta-diol disulfate, and glutamine might be associated with a decreased risk of AD, while sphingomyelin was associated with an increased risk. Side-effect profiles were characterized to help inform drug target prioritization, and glutamine might be a promising target for the prevention and treatment of AD with no predicted detrimental side effects. ANN NEUROL 2022;92:756-767.
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