Zhang Lu-Yang, Liu Yu-Xin, Chu Yun-Hui, You Yun-Fan, Zhou Luo-Qi, Yang Sheng, Dong Ming-Hao, Zhang Hang, Pang Xiao-Wei, Chen Lian, Zhu Li-Fang, Xiao Jun, Shang Ke, Wang Wei, Qin Chuan, Tian Dai-Shi
Department of Neurology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China.
Transl Psychiatry. 2025 Jun 25;15(1):214. doi: 10.1038/s41398-025-03437-w.
Cognitive dysfunction poses a significant challenge in clinical practice, but currently available drugs mainly address symptoms and have limited effectiveness in treating cognitive dysfunction associated with various neurological disorders. Mendelian randomization (MR) and colocalization analyses were conducted to explore the causal associations between 4302 druggable genes with blood and brain cis-expression quantitative trait loci (eQTLs) and cognitive performance. The causal effects of candidate druggable genes on brain structure and neurological diseases were assessed to gain insights into the underlying mechanisms. Among over 4000 druggable genes, our study identified causal associations between 72 druggable genes (41 blood eQTLs and 31 brain eQTLs) and cognitive performance. Thirteen eQTLs (six in blood: ERBB3, SPEG, ATP2A1, GDF11, CYP2D6, GANAB; seven in brain: ERBB3, DPYD, TAB1, WNT4, CLCN2, PPM1B, CAMKV) were identified as candidate druggable genes for cognitive performance. Notably, both blood and brain eQTLs of ERBB3 were negatively associated with cognitive performance (blood: OR = 0.933, 95% CI 0.911-0.956, p-value = 9.69E-09; brain: OR = 0.782, 95% CI 0.718-0.852, p-value = 2.13E-08). Moreover, these candidate druggable genes exhibited causal effects on both brain structure and neurological diseases. Our integrative analysis provides genetic evidence supporting candidate therapeutic targets for improving cognitive performance and treating neurological diseases. Furthermore, it sheds light on the possible mechanisms by which these targets affect brain structures. This finding suggested that these identified druggable genes, particularly ERBB3 and CYP2D6, hold promise as potential drug targets for enhancing cognitive performance.
认知功能障碍在临床实践中构成了重大挑战，但目前可用的药物主要针对症状，在治疗与各种神经系统疾病相关的认知功能障碍方面效果有限。进行了孟德尔随机化（MR）和共定位分析，以探索4302个可药物化基因与血液和大脑顺式表达定量性状位点（eQTL）之间的因果关联以及认知表现。评估了候选可药物化基因对脑结构和神经系统疾病的因果效应，以深入了解潜在机制。在4000多个可药物化基因中，我们的研究确定了72个可药物化基因（41个血液eQTL和31个大脑eQTL）与认知表现之间的因果关联。13个eQTL（血液中的6个：ERBB3、SPEG、ATP2A1、GDF11、CYP2D6、GANAB；大脑中的7个：ERBB3、DPYD、TAB1、WNT4、CLCN2、PPM1B、CAMKV）被确定为认知表现的候选可药物化基因。值得注意的是，ERBB3的血液和大脑eQTL均与认知表现呈负相关（血液：OR = 0.933，95%CI 0.911 - 0.956，p值 = 9.69E - 09；大脑：OR = 0.782，95%CI 0.718 - 0.852，p值 = 2.13E - 08）。此外，这些候选可药物化基因对脑结构和神经系统疾病均表现出因果效应。我们的综合分析提供了遗传证据，支持改善认知表现和治疗神经系统疾病的候选治疗靶点。此外，它揭示了这些靶点影响脑结构的可能机制。这一发现表明，这些已确定的可药物化基因，特别是ERBB3和CYP2D6，有望成为增强认知表现的潜在药物靶点。
