Laboratory of Neurodegenerative Disorders, Department of Neurology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
J Gerontol A Biol Sci Med Sci. 2024 Aug 1;79(8). doi: 10.1093/gerona/glae155.
Cognitive decline is among the most common non-motor symptoms in Parkinson's disease (PD), while its physiological mechanisms remain poorly understood. Genetic factors constituted a fundamental determinant in the heterogeneity of cognitive decline among PD patients. However, the underlying genetic background was still less studied.
To explore the genetic determinants contributing to cognitive decline in PD, we performed genome-wide survival analysis using a Cox proportional hazards model in a longitudinal cohort of 450 Chinese patients with PD, and further explored the functional effect of the target variant. Additionally, we built a clinical-genetic model by incorporating clinical characteristics and polygenic risk score (PRS) to predict cognitive decline in PD.
The cohort was followed up for an average of 5.25 (SE = 2.46) years, with 95 incidents of cognitive impairment. We identified significant association between locus rs75819919 (DPP6) and accelerated cognitive decline (p = 8.63E-09, beta = 1.74, SE = 0.30). Dual-luciferase reporter assay suggested this locus might be involved in the regulation of DPP6 expression. Using data set from the UK Biobank, we identified rs75819919 was associated with cognitive performance in the general population. Incorporation of PRS increased the model's predictability, achieving an average AUC of 75.6% through fivefold cross-validation in 1 000 iterations.
These findings improve the current understanding of the genetic etiology of cognitive impairment in PD, and provide a novel target DPP6 to explore therapeutic options. Our results also demonstrate the potential to develop clinical-genetic model to identify patients susceptible to cognitive impairment and thus provide personalized clinical guidance.
认知衰退是帕金森病（PD）中最常见的非运动症状之一，但其生理机制仍知之甚少。遗传因素是 PD 患者认知衰退异质性的基本决定因素。然而，潜在的遗传背景仍研究较少。
为了探讨导致 PD 患者认知衰退的遗传决定因素，我们使用 Cox 比例风险模型对 450 名中国 PD 患者的纵向队列进行了全基因组生存分析，并进一步探讨了目标变异的功能效应。此外，我们通过纳入临床特征和多基因风险评分（PRS）构建了一个临床遗传模型，以预测 PD 患者的认知衰退。
该队列的平均随访时间为 5.25 年（SE=2.46 年），有 95 例认知障碍事件。我们发现 rs75819919 （DPP6） 与认知衰退加速之间存在显著关联（p=8.63E-09，β=1.74，SE=0.30）。双荧光素酶报告基因检测提示该位点可能参与 DPP6 表达的调控。利用英国生物库（UK Biobank）的数据，我们发现 rs75819919 与一般人群的认知表现相关。PRS 的纳入提高了模型的预测能力，在 1000 次迭代的 5 倍交叉验证中，平均 AUC 达到 75.6%。
这些发现提高了我们对 PD 认知障碍遗传病因的认识，并提供了一个新的靶点 DPP6 来探索治疗选择。我们的研究结果还表明，有可能开发临床遗传模型来识别易患认知障碍的患者，从而为他们提供个性化的临床指导。
