Wang Ying, Song Xinhua, Wang Rui, Xu Xinzi, Du Yaming, Chen Guohua, Mei Junhua
Department of Neurology, Traditional Chinese and Western Medicine Hospital of Wuhan/Wuhan First Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Neurology, Wuhan First Hospital, Hubei University of Chinese Medicine, Wuhan, China.
J Alzheimers Dis Rep. 2024 Sep 5;8(1):1185-1197. doi: 10.3233/ADR-240062. eCollection 2024.
Alzheimer's disease (AD) currently lacks effective disease-modifying treatments. Recent research suggests that ferroptosis could be a potential therapeutic target. Mendelian randomization (MR) is a widely used method for identifying novel therapeutic targets.
Employ genetic information to evaluate the causal impact of ferroptosis-related genes on the risk of AD.
564 ferroptosis-related genes were obtained from FerrDb. We derived genetic instrumental variables for these genes using four brain quantitative trait loci (QTL) and two blood QTL datasets. Summary-data-based Mendelian randomization (SMR) and two-sample MR methods were applied to estimate the causal effects of ferroptosis-related genes on AD. Using extern transcriptomic datasets and triple-transgenic mouse model of AD (3xTg-AD) to further validate the gene targets identified by the MR analysis.
We identified 17 potential AD risk gene targets from GTEx, 13 from PsychENCODE, and 22 from BrainMeta (SMR < 0.05 and HEIDI test > 0.05). Six overlapping ferroptosis-related genes associated with AD were identified, which could serve as potential therapeutic targets and ). Additionally, we further pinpointed risk genes or proteins at the blood tissue and pQTL levels. Notably, demonstrated significant dysregulation in the extern transcriptomic datasets and 3xTg-AD models.
This study provides genetic evidence supporting the potential therapeutic benefits of targeting the six druggable genes for AD treatment, especially for (validated by transcriptome and 3xTg-AD), which could be useful for prioritizing AD drug development in the field of ferroptosis.
阿尔茨海默病（AD）目前缺乏有效的疾病修饰治疗方法。最近的研究表明，铁死亡可能是一个潜在的治疗靶点。孟德尔随机化（MR）是一种广泛用于识别新治疗靶点的方法。
利用遗传信息评估铁死亡相关基因对AD风险的因果影响。
从FerrDb中获取564个铁死亡相关基因。我们使用四个脑定量性状位点（QTL）和两个血液QTL数据集为这些基因推导遗传工具变量。应用基于汇总数据的孟德尔随机化（SMR）和两样本MR方法来估计铁死亡相关基因对AD的因果效应。使用外部转录组数据集和AD的三转基因小鼠模型（3xTg-AD）进一步验证MR分析确定的基因靶点。
我们从GTEx中鉴定出17个潜在的AD风险基因靶点，从PsychENCODE中鉴定出13个，从BrainMeta中鉴定出22个（SMR < 0.05且HEIDI检验> 0.05）。鉴定出六个与AD相关的重叠铁死亡相关基因，它们可作为潜在的治疗靶点 。此外，我们进一步在血液组织和pQTL水平上确定了风险基因或蛋白质。值得注意的是， 在外部转录组数据集和3xTg-AD模型中表现出明显的失调。
本研究提供了遗传证据，支持靶向这六个可药物化基因进行AD治疗的潜在治疗益处，特别是对于 （通过转录组和3xTg-AD验证），这可能有助于在铁死亡领域优先开展AD药物开发。
