Alpha-Synuclein (a-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of a-Syn are not currently used as a clinical biomarker but may be a proxy for pathological a-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF a-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF a-Syn levels remain unknown. CSF levels of amyloid beta1-42 (Ab42), total tau (t-tau), and phosphorylated tau181 (p-tau181) are standard biomarkers for the diagnosis of Alzheimer disease (AD); its use as quantitative traits in genetic studies have provided novel insights into AD pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in PD has not been conducted. Here, genome-wide association studies (GWAS) were performed using CSF biomarker levels as quantitative traits in four PD cases and control cohorts (combined N=1,960). CSF biomarker (a-Syn, Ab42, t-tau, and p-tau181) levels were significantly lower in PD cases compared with controls. An SNP, proxy for APOE e4, was associated with CSF Ab42 levels (effect=-0.5, p=9.2x10-19). Several genome-wide suggestive loci associated with CSF a-Syn, t-tau, or p-tau181 were found. Polygenic risk scores (PRS) were constructed using the latest PD risk meta-analysis (49,731 PD cases and 784,343 controls) and the largest CSF biomarkers GWAS (N=3,146). PRS calculated using META-PD were associated with PD status in the four cohorts included in the present study (p= 2.2x10-16). A highly significant correlation (Nagelkerke pseudo-R2 =2.29%; p=2.5x10-11) of the genomic architecture between CSF Ab42 and PD risk was also found. Higher PRS scores were associated with lower CSF Ab42 levels (p=7.3x10-04). Two-sample Mendelian Randomization (MR) approach revealed that CSF Ab42 plays a role in PD risk (p=1.4x10-05) and age at onset (p=7.6x10-06), an effect mainly mediated by variants in the APOE locus. Subsequently, the APOE e4 allele was associated with significantly lower levels of CSF Ab42 (p=3.8x10-06), higher mean cortical binding potentials (cortical binding of Pittsburgh compound B PET) (p=5.8x10-08) and higher Braak Ab; score (p=4.4x10-04) in PD participants. Together these results from high-throughput and hypothesis-free approaches (GWAS, PRS and MR) converge on a genetic link between PD with CSF Ab42 and APOE.

中文翻译：

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全基因组关联，孟德尔随机化和多基因风险评分研究集中于β-淀粉样蛋白和APOE基因座在帕金森病中的作用

α-突触核蛋白（α-Syn）是路易小体（LB）的主要蛋白质成分，这是帕金森氏病（PD）的病理标志。a-Syn的脑脊髓液（CSF）水平目前尚未用作临床生物标志物，但可能是脑中病理性a-Syn积累的代表。因此，鉴定CSF a-Syn水平的遗传修饰剂可以提供导致PD的潜在分子机制的见解。但是，CSF a-Syn水平的遗传修饰因子仍然未知。淀粉样蛋白β1-42（Ab42），总tau（t-tau）和磷酸化tau181（p-tau181）的CSF水平是诊断阿尔茨海默病（AD）的标准生物标志物；它在基因研究中作为定量性状的应用为AD病理生理学提供了新颖的见解。尚未对PD中CSF生物标志物的基因组结构进行系统研究。在这里，使用CSF生物标志物水平作为定量特征对4个PD病例和对照队列（合并N = 1,960）进行了全基因组关联研究（GWAS）。与对照组相比，PD患者的CSF生物标志物（α-Syn，Ab42，t-tau和p-tau181）水平显着降低。SNP（APOE e4的代理）与CSF Ab42水平相关（效果= -0.5，p = 9.2x10-19）。发现了几个与CSF a-Syn，t-tau或p-tau181相关的全基因组提示位点。使用最新的PD风险荟萃分析（49,731个PD病例和784,343个对照）和最大的CSF生物标志物GWAS（N = 3,146）构建了多基因风险评分（PRS）。使用META-PD计算的PRS与本研究中包括的四个队列中的PD状态相关（p = 2.2x10-16）。高度相关（Nagelkerke伪R2 = 2.29％; p = 2。还发现了CSF Ab42和PD风险之间的基因组结构的5x10-11）。较高的PRS评分与较低的CSF Ab42水平相关（p = 7.3x10-04）。孟德尔随机抽样（MR）的两个样本显示，CSF Ab42在PD风险（p = 1.4x10-05）和发病年龄（p = 7.6x10-06）中起作用，该作用主要由APOE基因座的变异介导。随后，APOE e4等位基因与脑脊液Ab42的水平显着降低（p = 3.8x10-06），平均皮质结合电位（匹兹堡化合物B PET的皮质结合）（p = 5.8x10-08）和Braak Ab升高相关; PD参与者的得分（p = 4.4x10-04）。高通量和无假设方法（GWAS，PRS和MR）的这些结果共同融合在PD与CSF Ab42和APOE之间的遗传联系上。较高的PRS评分与较低的CSF Ab42水平相关（p = 7.3x10-04）。孟德尔随机抽样（MR）的两个样本显示，CSF Ab42在PD风险（p = 1.4x10-05）和发病年龄（p = 7.6x10-06）中起作用，该作用主要由APOE基因座的变异介导。随后，APOE e4等位基因与脑脊液Ab42的水平显着降低（p = 3.8x10-06），平均皮质结合电位（匹兹堡化合物B PET的皮质结合）（p = 5.8x10-08）和Braak Ab升高相关; PD参与者的得分（p = 4.4x10-04）。高通量和无假设方法（GWAS，PRS和MR）的这些结果共同融合在PD与CSF Ab42和APOE之间的遗传联系上。较高的PRS评分与较低的CSF Ab42水平相关（p = 7.3x10-04）。孟德尔随机抽样（MR）的两个样本显示，CSF Ab42在PD风险（p = 1.4x10-05）和发病年龄（p = 7.6x10-06）中起作用，该作用主要由APOE基因座的变异介导。随后，APOE e4等位基因与脑脊液Ab42的水平显着降低（p = 3.8x10-06），平均皮质结合电位（匹兹堡化合物B PET的皮质结合）（p = 5.8x10-08）和Braak Ab升高相关; PD参与者的得分（p = 4.4x10-04）。这些来自高通量和无假设方法（GWAS，PRS和MR）的结果共同融合在PD与CSF Ab42和APOE之间的遗传联系上。4x10-05）和发病年龄（p = 7.6x10-06），这种影响主要由APOE位点的变异介导。随后，APOE e4等位基因与脑脊液Ab42的水平显着降低（p = 3.8x10-06），平均皮质结合电位（匹兹堡化合物B PET的皮质结合）（p = 5.8x10-08）和Braak Ab升高相关; PD参与者的得分（p = 4.4x10-04）。高通量和无假设方法（GWAS，PRS和MR）的这些结果共同融合在PD与CSF Ab42和APOE之间的遗传联系上。4x10-05）和发病年龄（p = 7.6x10-06），这种影响主要由APOE位点的变异介导。随后，APOE e4等位基因与脑脊液Ab42的水平显着降低（p = 3.8x10-06），平均皮质结合电位（匹兹堡化合物B PET的皮质结合）（p = 5.8x10-08）和Braak Ab升高相关; PD参与者的得分（p = 4.4x10-04）。高通量和无假设方法（GWAS，PRS和MR）的这些结果共同融合在PD与CSF Ab42和APOE之间的遗传联系上。4x10-04）。高通量和无假设方法（GWAS，PRS和MR）的这些结果共同融合在PD与CSF Ab42和APOE之间的遗传联系上。4x10-04）。这些来自高通量和无假设方法（GWAS，PRS和MR）的结果共同融合在PD与CSF Ab42和APOE之间的遗传联系上。