Qian Ruiyi, Zhao Xue, Lyu Dongbin, Xu Qingqing, Yuan Kai, Luo Xin, Wang Wanying, Wang Yang, Liu Yutong, Cheng Yu, Tan Yingting, Mou Fan, Yuan Chengmei, Yu Shunying
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Institute of Digestive Disease, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
Pharmaceuticals (Basel). 2024 Dec 4;17(12):1626. doi: 10.3390/ph17121626.
Restless legs syndrome (RLS) is a common sensorimotor sleep disorder that affects sleep quality of life. Much effort has been made to make progress in RLS pharmacotherapy; however, patients with RLS still report poor long-term symptom control. Comprehensive Mendelian randomization (MR) was performed to search for potential causal genes and drug targets using the cis-pQTL and RLS GWAS data. Robustness was validated using the summary-based Mendelian randomization (SMR) method and co-localization analysis. Further evidence of pleiotropy of the target genes and their potential side effects was provided by phenome-wide MR analysis (MR-PheWAS). Finally, molecular docking simulations were conducted on drug candidates corresponding to these targets, which revealed promising binding affinities and interaction patterns and underscored the druggable potential of the target gene. All of the analyses above were conducted in the context of . showed a statistically significant result in the MR analysis, which was validated through SMR and co-localization analysis. The MR-PheWAS showed a low probability of pleiotropy and prospective side effects. Molecular docking was used to visualize the binding structure and fine affinity for and the drugs predicted by DSigDB. Our study provides comprehensive evidence supporting as a promising causal gene and therapeutic target for RLS, offering insights into the underlying molecular mechanisms and paving the way for future drug development efforts.
不宁腿综合征（RLS）是一种常见的感觉运动性睡眠障碍，会影响睡眠质量和生活质量。人们在RLS药物治疗方面付出了很多努力以取得进展；然而，RLS患者仍报告长期症状控制不佳。利用顺式pQTL和RLS全基因组关联研究（GWAS）数据进行了综合孟德尔随机化（MR）分析，以寻找潜在的因果基因和药物靶点。使用基于汇总数据的孟德尔随机化（SMR）方法和共定位分析验证了结果的稳健性。全表型孟德尔随机化分析（MR-PheWAS）提供了目标基因多效性及其潜在副作用的进一步证据。最后，对与这些靶点对应的候选药物进行了分子对接模拟，结果显示出有前景的结合亲和力和相互作用模式，并强调了目标基因的可成药潜力。上述所有分析均在……背景下进行。……在MR分析中显示出具有统计学意义的结果，并通过SMR和共定位分析得到验证。MR-PheWAS显示多效性和潜在副作用的可能性较低。分子对接用于可视化……以及DSigDB预测的药物的结合结构和精细亲和力。我们的研究提供了全面的证据，支持……作为RLS一个有前景的因果基因和治疗靶点，为潜在的分子机制提供了见解，并为未来的药物开发努力铺平了道路。
