Data_Sheet_1_Genomic Association Study for Cognitive Impairment in Parkinson's Disease.docx

Background: Cognitive impairment is very common in Parkinson's disease (PD) and constitutes the most debilitating complication of this disease. However, to date, few studies have investigated a genome-wide association in the development of cognitive impairment of PD. We aimed to identify the genetic loci associated with cognitive impairment in patients with sporadic PD by ethnicity-specific genotyping.
Materials and methods: We recruited 1,070 patients with PD and performed a genome-wide association study using the Korean Chip, a microarray chip containing 827,400 single-nucleotide polymorphisms (SNPs) optimized for the Korean population. Multiple logistic regression models adjusting for age, sex, years of education, and disease duration were used to compare between patients with and without cognitive impairment, which was defined using the Mini-Mental Status Examination (MMSE) score (MMSE score ≥ 26 vs. < 26) or the Montreal Cognitive Assessment (MoCA) score (MoCA score ≥24 vs. < 24).
Results:RYR2 SNP rs10495397 was most significantly associated with cognitive impairment based on the MMSE scores (OR = 3.21; 95% CI = 1.96–5.25, P = 3.36 × 10−6) and CASC17 showed the strongest association with cognitive impairment based on the MoCA scores. However, none of the SNPs were statistically significant after Bonferroni correction.
Conclusion:RYR2 may play a role in cognitive impairment in PD by the pathogenic mechanism of neuroinflammation. However, more studies are needed to replicate and validate the results of our functional study.

背景：认知功能障碍在帕金森病（Parkinson's disease, PD）中极为常见，是该病最具致残性的并发症。然而截至目前，鲜有研究探讨帕金森病认知障碍发生发展过程中的全基因组关联分析。本研究旨在通过种族特异性基因分型，鉴定散发性帕金森病患者中与认知功能障碍相关的遗传位点。
材料与方法：本研究纳入1070例帕金森病患者，采用针对韩国人群优化的、包含827400个单核苷酸多态性（single-nucleotide polymorphisms, SNPs）的微阵列芯片——韩国定制基因芯片（Korean Chip）开展全基因组关联分析。以年龄、性别、受教育年限及病程为协变量构建多因素logistic回归模型，对比存在与不存在认知功能障碍的患者差异；认知功能障碍的判定标准为：简易精神状态检查（Mini-Mental Status Examination, MMSE）评分≥26分（异常组）与<26分（正常组），或蒙特利尔认知评估（Montreal Cognitive Assessment, MoCA）评分≥24分（异常组）与<24分（正常组）。
结果：基于MMSE评分分析，RYR2基因的rs10495397位点与帕金森病认知功能障碍的关联最为显著（比值比odds ratio, OR=3.21，95%置信区间confidence interval, CI=1.96~5.25，P=3.36×10^-6）；基于MoCA评分分析，CASC17基因与认知功能障碍的关联强度最高。但经邦费罗尼校正（Bonferroni correction）后，所有SNP位点均无统计学显著性。
结论：RYR2可能通过神经炎症的致病机制参与帕金森病患者的认知功能障碍发生过程。然而，本研究的功能学结果仍需更多研究进行重复与验证。