Abstract：
OBJECTIVE: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data.
METHODS: Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets.
RESULTS: Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD.
CONCLUSIONS: Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.
METHODS: Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets.
RESULTS: Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD.
CONCLUSIONS: Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.
摘要：
目的：散发性Creutzfeldt-Jakob病（sCJD）是一种致命的快速进行性神经退行性疾病，没有有效的治疗干预措施。我们旨在通过整合多组学数据来确定sCJD的潜在遗传支持药物靶标。
方法：多组学范围关联研究，孟德尔随机化，和共定位分析被用来探索潜在的治疗靶标，使用表达，单细胞表达，DNA甲基化，以及来自血液和脑组织的蛋白质数量性状基因座数据。结果数据来自病例对照全基因组关联研究，其中包括4110名sCJD患者和13,569名对照。进一步的调查包括可药用性，潜在的副作用,和相关的生物途径确定的目标。
结果：综合多组学分析确定了sCJD的23个潜在治疗靶点，五个目标（STX6，XYLT2，PDIA4，FUCA2，KIAA1614）具有更高水平的证据。一个目标（XYLT2）显示出重新利用的希望，两个目标（XYLT2，PDIA4）是可吸毒的，三个（STX6，KIAA1614和FUCA2）目标代表了潜在的未来突破口。STX6和XYLT2在神经元和少突胶质细胞中的表达水平与sCJD的风险增加密切相关。STX6高表达或与sCJD有因果关系的脑区通常是那些通常受sCJD影响的区域。
结论：我们的研究确定了sCJD的五个潜在治疗靶点。需要进一步的研究以阐明开发疾病疗法或启动临床试验的新靶标的潜在机制。
方法：多组学范围关联研究，孟德尔随机化，和共定位分析被用来探索潜在的治疗靶标，使用表达，单细胞表达，DNA甲基化，以及来自血液和脑组织的蛋白质数量性状基因座数据。结果数据来自病例对照全基因组关联研究，其中包括4110名sCJD患者和13,569名对照。进一步的调查包括可药用性，潜在的副作用,和相关的生物途径确定的目标。
结果：综合多组学分析确定了sCJD的23个潜在治疗靶点，五个目标（STX6，XYLT2，PDIA4，FUCA2，KIAA1614）具有更高水平的证据。一个目标（XYLT2）显示出重新利用的希望，两个目标（XYLT2，PDIA4）是可吸毒的，三个（STX6，KIAA1614和FUCA2）目标代表了潜在的未来突破口。STX6和XYLT2在神经元和少突胶质细胞中的表达水平与sCJD的风险增加密切相关。STX6高表达或与sCJD有因果关系的脑区通常是那些通常受sCJD影响的区域。
结论：我们的研究确定了sCJD的五个潜在治疗靶点。需要进一步的研究以阐明开发疾病疗法或启动临床试验的新靶标的潜在机制。
