GWAS Identifies DPP6 as Risk Gene of Cognitive Decline in Parkinson’s Disease

作者：Chunyu Li, Yanbing Hou, Ruwei Ou, Qianqian Wei, Lingyu Zhang, Kuncheng Liu, Junyu Lin, Xueping Chen, Wei Song, Bi Zhao, Ying Wu, Huifang Shang · 发表于：The Journals of Gerontology Series A · 年份：2024 · DOI：10.1093/gerona/glae155 · 被引用次数：7 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Genetic Associations and Epidemiology、Nuclear Receptors and Signaling

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 unders...