PDF(Pubmed)
Abstract：
UNASSIGNED: Parkinson\'s disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear.
UNASSIGNED: This study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson\'s disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson\'s Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD.
UNASSIGNED: Elevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, p = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, p = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, p = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, p < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005).
UNASSIGNED: This genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.
UNASSIGNED: This study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson\'s disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson\'s Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD.
UNASSIGNED: Elevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, p = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, p = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, p = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, p < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005).
UNASSIGNED: This genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.
摘要：
■帕金森病（PD），第二个最普遍的神经退行性疾病，有多方面的病因。位于溶酶体内的组织蛋白酶-半胱氨酸蛋白酶参与一系列生理和病理过程，包括有害蛋白质的降解。先前的研究指出了组织蛋白酶和PD之间的潜在联系；然而，组织蛋白酶家族与PD之间的确切因果关系尚不清楚.
■本研究采用单变量和多变量孟德尔随机化(MR)分析来探讨9种组织蛋白酶与帕金森病(PD)风险之间的因果关系。对于主要分析，来自INTERVAL研究和国际帕金森病基因组学联盟的9种组织蛋白酶和PD血浆水平的全基因组关联研究(GWAS)汇总统计.用于PD复制分析的GWAS是从FinnGen联盟获得的，我们对初级分析和复制分析进行了荟萃分析,以评估基因预测的组织蛋白酶血浆水平与PD风险之间的关联.在确定了重要的MR估计后，我们进行了基因共定位分析,以确定共有或不同的因果变异是否同时影响组织蛋白酶和PD.
■单变量MR分析显示，组织蛋白酶B水平升高与PD风险降低相关（比值比[OR]=0.890，95%置信区间[CI]：0.831-0.954，pFDR=0.009）。然而,没有迹象表明PD会影响组织蛋白酶B水平(OR=0.965,95%CI:0.858-1.087,p=0.852).此外,在调整剩余的组织蛋白酶后，在多变量MR分析中,组织蛋白酶B水平独立且显著地降低了PD的风险(OR=0.887,95%CI:0.823-0.957,p=0.002).使用FinnGenGWAS进行PD的复制MR分析（OR=0.921，95％CI：0.860-0.987，p=0.020）和荟萃分析（OR=0.905，95％CI：0.862-0.951，p<0.001）的结果与主要分析的结果一致。共定位分析没有提供任何证据表明组织蛋白酶和PD之间存在共同的因果变异（PP。H4.abf=0.005)。
■该遗传研究支持组织蛋白酶B对PD具有保护作用的假设。组织蛋白酶B水平的定量可能作为PD易感性的预测生物标志物，提供对疾病的病理机制和可能的干预措施的新见解。
■本研究采用单变量和多变量孟德尔随机化(MR)分析来探讨9种组织蛋白酶与帕金森病(PD)风险之间的因果关系。对于主要分析，来自INTERVAL研究和国际帕金森病基因组学联盟的9种组织蛋白酶和PD血浆水平的全基因组关联研究(GWAS)汇总统计.用于PD复制分析的GWAS是从FinnGen联盟获得的，我们对初级分析和复制分析进行了荟萃分析,以评估基因预测的组织蛋白酶血浆水平与PD风险之间的关联.在确定了重要的MR估计后，我们进行了基因共定位分析,以确定共有或不同的因果变异是否同时影响组织蛋白酶和PD.
■单变量MR分析显示，组织蛋白酶B水平升高与PD风险降低相关（比值比[OR]=0.890，95%置信区间[CI]：0.831-0.954，pFDR=0.009）。然而,没有迹象表明PD会影响组织蛋白酶B水平(OR=0.965,95%CI:0.858-1.087,p=0.852).此外,在调整剩余的组织蛋白酶后，在多变量MR分析中,组织蛋白酶B水平独立且显著地降低了PD的风险(OR=0.887,95%CI:0.823-0.957,p=0.002).使用FinnGenGWAS进行PD的复制MR分析（OR=0.921，95％CI：0.860-0.987，p=0.020）和荟萃分析（OR=0.905，95％CI：0.862-0.951，p<0.001）的结果与主要分析的结果一致。共定位分析没有提供任何证据表明组织蛋白酶和PD之间存在共同的因果变异（PP。H4.abf=0.005)。
■该遗传研究支持组织蛋白酶B对PD具有保护作用的假设。组织蛋白酶B水平的定量可能作为PD易感性的预测生物标志物，提供对疾病的病理机制和可能的干预措施的新见解。
