Department of Neurology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China (X.-Z.Y., M.-Y.H., F.H., J.-N., L.-X.Z., M.Y., D.-D.Z., Y.-C.Z.).
Center for Bioinformatics, National Infrastructures for Translational Medicine, Institute of Clinical Medicine & Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China (X.-Z.Y.).
Stroke. 2024 Sep;55(9):2264-2273. doi: 10.1161/STROKEAHA.124.046544. Epub 2024 Aug 8.
Cerebral small vessel disease (CSVD) is a group of neurological disorders that affect the small blood vessels within the brain, for which no effective treatments are currently available. We conducted a Mendelian randomization (MR) study to identify candidate therapeutic genes for CSVD.
We retrieved genome-wide association study data from 6 recently conducted, extensive investigations focusing on CSVD magnetic resonance imaging markers and performed a 2-sample MR analysis to assess the potential causal effects of gene expression and protein level within druggable genes on CSVD in blood and brain tissues. Colocalization analyses and repeat studies were undertaken to verify the relationship. Additionally, mediation analysis was conducted to explore the potential mechanisms involving druggable genes and known risk factors for CSVD. Finally, phenome-wide MR analyses were applied to evaluate the potential adverse effects related to the identified druggable genes for CSVD treatment.
Overall, 5 druggable genes consistently showed associations with CSVD in MR analyses across both the discovery and validation cohorts. Notably, the and genes were identified as associated with CSVD in both blood and brain tissues, whereas the genes , , and were exclusively detected in brain tissue. Moreover, mediation analysis elucidated the proportion of the total effects mediated by CSVD risk factors through candidate druggable genes, which ranged from 5.5% to 18.5%, and offered potential explanations for the observed results. A comprehensive phenome-wide MR analysis further emphasized both the therapeutic benefits and potential side effects of targeting these candidate druggable genes.
This study provides genetic evidence supporting the potential therapeutic benefits of targeting druggable genes for treating CSVD, which will be useful for prioritizing CSVD drug development.
脑小血管病（CSVD）是一组影响脑内小血管的神经系统疾病，目前尚无有效的治疗方法。我们进行了一项孟德尔随机化（MR）研究，以确定 CSVD 的候选治疗基因。
我们从最近进行的 6 项针对 CSVD 磁共振成像标志物的广泛研究中检索了全基因组关联研究数据，并进行了 2 样本 MR 分析，以评估血液和脑组织中可药物治疗基因的基因表达和蛋白水平对 CSVD 的潜在因果影响。进行了共定位分析和重复研究以验证这种关系。此外，还进行了中介分析以探索涉及可药物治疗基因和 CSVD 已知风险因素的潜在机制。最后，进行了表型广泛的 MR 分析，以评估与 CSVD 治疗相关的可药物治疗基因的潜在不良反应。
总体而言，在发现和验证队列的 MR 分析中，有 5 个可药物治疗基因在 CSVD 中表现出一致的关联。值得注意的是，基因和基因与血液和脑组织中的 CSVD 均有关联，而基因、、和则仅在脑组织中被检测到。此外，中介分析阐明了 CSVD 风险因素通过候选可药物治疗基因介导的总效应的比例，范围为 5.5%至 18.5%，并为观察到的结果提供了潜在的解释。全面的表型广泛的 MR 分析进一步强调了针对这些候选可药物治疗基因的治疗益处和潜在的副作用。
本研究提供了遗传证据，支持针对可药物治疗基因治疗 CSVD 的潜在治疗益处，这将有助于优先考虑 CSVD 药物开发。
