Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 plays a role in Parkinson’s disease (p = 1.4 × 10−05) and age at onset (p = 7.6 × 10−06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1–42 (p = 3.8 × 10−06), higher mean cortical binding potentials (p = 5.8 × 10−08), and higher Braak amyloid beta score (p = 4.4 × 10−04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta1–42, and APOE.

中文翻译：

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功能基因组分析揭示了 APOE 介导的帕金森病大脑和脑脊液 β-淀粉样蛋白水平的调节

α-突触核蛋白是路易体的主要蛋白质成分，路易体是帕金森病的病理标志。然而，脑脊液 (CSF) α-突触核蛋白水平的遗传修饰因素仍然未知。在基因研究中使用脑脊液中淀粉样蛋白 β1-42、总 tau 和磷酸化 tau181 的水平作为数量性状，为阿尔茨海默病的病理生理学提供了新的见解。尚未对帕金森病脑脊液生物标志物的基因组结构进行系统研究。在这里，对一组帕金森病患者和对照组（N = 1960）的脑脊液生物标志物水平进行了全基因组关联研究。与对照组相比，PD 病例的脑脊液生物标志物水平显着降低。SNP（APOE ε4 的代表）与 CSF 淀粉样蛋白 beta1-42 水平相关（效应 = − 0.5，p = 9.2 × 10−19）。在 PD 队列中未发现与 CSF α-突触核蛋白、总 tau 或磷酸化 tau181 水平相关的全基因组位点。使用最新的帕金森病风险荟萃分析构建的多基因风险评分与帕金森病状态 (p = 0.035) 和脑脊液淀粉样蛋白 beta1-42 的基因组结构相关 (R2 = 2.29%; p = 2.5 × 10−11)。PD 风险多基因风险评分较高的个体脑脊液淀粉样蛋白 beta1-42 水平较低 (p = 7.3 × 10−04)。两个样本孟德尔随机化显示，脑脊液淀粉样蛋白 beta1-42 在帕金森病 (p = 1.4 × 10−05) 和发病年龄 (p = 7.6 × 10−06) 中发挥作用，这种作用主要由 APOE 变异介导轨迹。在 PD 样本的子集中，APOE ε4 等位基因与脑脊液淀粉样蛋白 beta1-42 水平显着降低 (p = 3.8 × 10−06)、较高的平均皮质结合电位 (p = 5.8 × 10−08) 和较高的脑脊液淀粉样蛋白水平相关。 Braak 淀粉样蛋白 β 评分 (p = 4.4 × 10−04)。这些来自高通量和无假设方法的结果共同表明帕金森病、脑脊液淀粉样蛋白 beta1-42 和 APOE 之间存在遗传联系。