Department of Agricultural Genetic Engineering, Ayhan Şahenk Faculty of Agricultural Sciences and Technologies, Niğde Ömer Halisdemir University, Niğde, Turkey.
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Neurobiol Aging. 2022 Dec;120:167-176. doi: 10.1016/j.neurobiolaging.2022.09.004. Epub 2022 Sep 15.
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease caused by a combination of genetic and environmental risk factors. The serum metabolome refers to a set of small-molecules which are an important determinant of cellular health. We obtained genome-wide association study (GWAS) summary statistics for serum concentrations of 376 metabolites which were population matched with 2 GWAS studies of AD. For each metabolite we performed 2-sample MR (2SMR) using an inverse variance weighted (IVW) estimate for significance testing. After Bonferroni multiple testing correction one metabolite was causally linked to AD in both GWAS: serum urate. This result was supported by robust 2SMR measures and sensitivity analyses. We applied 2SMR to test for a causal relationship between serum urate and other neurodegenerative diseases: Parkinson disease (PD) and Amyotrophic lateral sclerosis (ALS). In ALS but not PD we identified a nominally significant link between serum urate and disease-risk, although in this case increased serum urate was protective. We conclude that serum urate is a modulator of risk for neurodegeneration. Our work has implications for the design of preventative interventions.
阿尔茨海默病（AD）是一种由遗传和环境风险因素共同引起的进行性和致命性神经退行性疾病。血清代谢组学是指一组小分子，是细胞健康的重要决定因素。我们获得了与 AD 的 2 项 GWAS 研究进行人群匹配的 376 种代谢物血清浓度的全基因组关联研究（GWAS）汇总统计数据。对于每种代谢物，我们使用逆方差加权（IVW）估计值进行了 2 样本 MR（2SMR），以进行显著性检验。经过 Bonferroni 多重测试校正，有 1 种代谢物在两项 GWAS 中与 AD 存在因果关系：血清尿酸。这一结果得到了稳健的 2SMR 措施和敏感性分析的支持。我们应用 2SMR 来检验血清尿酸与其他神经退行性疾病（帕金森病[PD]和肌萎缩侧索硬化症[ALS]）之间的因果关系。在 ALS 中，但不是在 PD 中，我们发现血清尿酸与疾病风险之间存在名义上的关联，尽管在这种情况下，血清尿酸的增加具有保护作用。我们得出结论，血清尿酸是神经变性风险的调节剂。我们的工作对预防性干预措施的设计具有重要意义。
