Mata Ignacio F, Johnson Catherine O, Leverenz James B, Weintraub Daniel, Trojanowski John Q, Van Deerlin Vivianna M, Ritz Beate, Rausch Rebecca, Factor Stewart A, Wood-Siverio Cathy, Quinn Joseph F, Chung Kathryn A, Peterson-Hiller Amie L, Espay Alberto J, Revilla Fredy J, Devoto Johnna, Yearout Dora, Hu Shu-Ching, Cholerton Brenna A, Montine Thomas J, Edwards Karen L, Zabetian Cyrus P
Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
Department of Epidemiology, School of Medicine, University of California Irvine, Irvine, CA, USA.
Neurobiol Aging. 2017 Aug;56:211.e1-211.e7. doi: 10.1016/j.neurobiolaging.2017.04.009. Epub 2017 Apr 20.
Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants, we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate-corrected p-value (P) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; P = 2.7 × 10) for JoLO, PARP4 rs9318600 (P = 0.006), and rs9581094 (P = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (P = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.
认知障碍是帕金森病（PD）中常见且致残的问题。识别影响PD认知缺陷的存在或严重程度的基因变异，可能有助于更清楚地了解这一重要非运动特征背后的病理生理学。我们使用NeuroX芯片对来自帕金森病认知遗传学联盟的1105名PD患者的249,336个变异进行了基因分型。参与者接受了学习和记忆评估（修订版霍普金斯词语学习测验[HVLT-R]）、工作记忆/执行功能评估（字母数字排序和连线测验[TMT]A和B）、语言处理评估（语义和音素言语流畅性）、视觉空间能力评估（本顿直线方向判断[JoLO]）以及整体认知功能评估（蒙特利尔认知评估）。对于常见变异，我们使用线性回归来测试基因型与认知表现之间的关联，并对重要协变量进行校正。使用最优统一序列核关联检验分析罕见变异。显著性阈值定义为错误发现率校正后的p值（P）为0.05。13个基因组区域中的18个常见变异在一项认知测试中超过了显著性阈值。其中包括JoLO的GBA rs2230288（E326K；P = 2.7×10）、HVLT-R总回忆的PARP4 rs9318600（P = 0.006）和rs9581094（P = 0.006），以及TMT B-A的MTCL1 rs34877994（P = 0.01）。对罕见变异的分析未产生任何显著的基因区域。我们进行了首次大规模的PD认知遗传学分析，并确定了几个新的可能导致PD认知障碍的易感基因。这些结果需要在独立的PD队列中进行重复验证。
