Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
Ann Neurol. 2024 Jul;96(1):133-149. doi: 10.1002/ana.26949. Epub 2024 May 20.
The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear-encoded mitochondrial genes ultimately resulting in neurodegeneration.
We used mitochondria-specific polygenic risk scores (mitoPRSs) and created pathway-specific mitoPRSs using genotype data from different iPD case-control datasets worldwide, including the Luxembourg Parkinson's Study (412 iPD patients and 576 healthy controls) and COURAGE-PD cohorts (7,270 iPD cases and 6,819 healthy controls). Cellular models from individuals stratified according to the most significant mitoPRS were subsequently used to characterize different aspects of mitochondrial function.
Common variants in genes regulating Oxidative Phosphorylation (OXPHOS-PRS) were significantly associated with a higher PD risk in independent cohorts (Luxembourg Parkinson's Study odds ratio, OR = 1.31[1.14-1.50], p-value = 5.4e-04; COURAGE-PD OR = 1.23[1.18-1.27], p-value = 1.5e-29). Functional analyses in fibroblasts and induced pluripotent stem cells-derived neuronal progenitors revealed significant differences in mitochondrial respiration between iPD patients with high or low OXPHOS-PRS (p-values < 0.05). Clinically, iPD patients with high OXPHOS-PRS have a significantly earlier age at disease onset compared to low-risk patients (false discovery rate [FDR]-adj p-value = 0.015), similar to prototypic monogenic forms of PD. Finally, iPD patients with high OXPHOS-PRS responded more effectively to treatment with mitochondrially active ursodeoxycholic acid.
OXPHOS-PRS may provide a precision medicine tool to stratify iPD patients into a pathogenic subgroup genetically defined by specific mitochondrial impairment, making these individuals eligible for future intelligent clinical trial designs. ANN NEUROL 2024;96:133-149.
本研究旨在深入了解特发性帕金森病（iPD）中神经退行性变的遗传结构和病理机制。我们假设，一部分 iPD 患者可能携带核编码线粒体基因的常见变异组合，最终导致神经退行性变。
我们使用线粒体特异性多基因风险评分（mitoPRSs），并使用来自世界各地不同 iPD 病例对照数据集的基因型数据创建了特定途径的 mitoPRSs，包括卢森堡帕金森研究（412 例 iPD 患者和 576 例健康对照）和 COURAGE-PD 队列（7270 例 iPD 病例和 6819 例健康对照）。随后，根据最显著的 mitoPRS 对个体进行分层，使用细胞模型来表征线粒体功能的不同方面。
调节氧化磷酸化（OXPHOS-PRS）的基因中的常见变异与独立队列中更高的 PD 风险显著相关（卢森堡帕金森研究的优势比，OR=1.31[1.14-1.50]，p 值=5.4e-04；COURAGE-PD 的 OR=1.23[1.18-1.27]，p 值=1.5e-29）。在成纤维细胞和诱导多能干细胞衍生的神经元祖细胞中的功能分析显示，OXPHOS-PRS 高或低的 iPD 患者之间线粒体呼吸存在显著差异（p 值<0.05）。临床上，OXPHOS-PRS 高的 iPD 患者的疾病发病年龄明显早于低风险患者（错误发现率 [FDR]-adj p 值=0.015），与典型的 PD 单基因形式相似。最后，OXPHOS-PRS 高的 iPD 患者对具有线粒体活性的熊去氧胆酸的治疗反应更有效。
OXPHOS-PRS 可能为 iPD 患者提供一种精准医学工具，将其分为遗传定义的特定线粒体损伤的致病亚组，使这些患者有资格参加未来的智能临床试验设计。神经病学年鉴 2024；96：133-149。
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