PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：认知功能减退是帕金森病（PD）最常见的非运动症状，而其生理机制仍然知之甚少。遗传因素是PD患者认知下降异质性的基本决定因素。然而,潜在的遗传背景研究仍然较少。
方法：为了探索导致PD认知能力下降的遗传决定因素，我们使用Cox比例风险模型在450名中国PD患者的纵向队列中进行了全基因组生存分析，并进一步探讨了目标变体的功能效应。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的认知功能下降.
结果：对该队列进行了平均5.25（SE=2.46）年的随访，95例认知障碍事件。我们确定了rs75819919（DPP6）基因座与加速认知下降之间的显着关联（P=8.63E-09，β=1.74，SE=0.30）。双荧光素酶报告基因分析提示该基因座可能参与DPP6表达的调节。使用英国生物银行的数据集，我们发现rs75819919与一般人群的认知能力相关.PRS的并入增加了模型的可预测性，在1,000次迭代中通过5倍交叉验证实现75.6%的平均AUC。
结论：这些发现提高了目前对PD认知障碍遗传病因的认识，并提供了一个新的靶点DPP6来探索治疗方案。我们的结果还证明了开发临床遗传模型以识别易患认知障碍的患者的潜力，从而提供个性化的临床指导。
方法：为了探索导致PD认知能力下降的遗传决定因素，我们使用Cox比例风险模型在450名中国PD患者的纵向队列中进行了全基因组生存分析，并进一步探讨了目标变体的功能效应。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的认知功能下降.
结果：对该队列进行了平均5.25（SE=2.46）年的随访，95例认知障碍事件。我们确定了rs75819919（DPP6）基因座与加速认知下降之间的显着关联（P=8.63E-09，β=1.74，SE=0.30）。双荧光素酶报告基因分析提示该基因座可能参与DPP6表达的调节。使用英国生物银行的数据集，我们发现rs75819919与一般人群的认知能力相关.PRS的并入增加了模型的可预测性，在1,000次迭代中通过5倍交叉验证实现75.6%的平均AUC。
结论：这些发现提高了目前对PD认知障碍遗传病因的认识，并提供了一个新的靶点DPP6来探索治疗方案。我们的结果还证明了开发临床遗传模型以识别易患认知障碍的患者的潜力，从而提供个性化的临床指导。
