可塑性相关基因3（）与帕金森病的诊断年龄
Plasticity-related gene 3 () and age at diagnosis of Parkinson disease.
作者信息
Wallen Zachary D, Chen Honglei, Hill-Burns Erin M, Factor Stewart A, Zabetian Cyrus P, Payami Haydeh
机构信息
Department of Neurology (Z.D.W., E.M.H.-B., H.P.), University of Alabama at Birmingham, Birmingham, AL; Department of Epidemiology and Biostatistics (H.C.), Michigan State University, East Lansing, MI; Department of Neurology (S.A.F.), Jean & Paul Amos Parkinson's Disease and Movement Disorder Program, Emory University School of Medicine, Atlanta, GA; VA Puget Sound Health Care System and Department of Neurology (C.P.Z.), University of Washington, Seattle, WA; and Center for Genomic Medicine (H.P.), HudsonAlpha Institute for Biotechnology, Huntsville, AL.
出版信息
Neurol Genet. 2018 Oct 5;4(5):e271. doi: 10.1212/NXG.0000000000000271. eCollection 2018 Oct.
OBJECTIVE
To identify modifiers of age at diagnosis of Parkinson disease (PD).
METHODS
Genome-wide association study (GWAS) included 1,950 individuals with PD from the NeuroGenetics Research Consortium (NGRC) study. Replication was conducted in the Parkinson's, Genes and Environment study, including 209 prevalent (PAGE) and 517 incident (PAGE) PD cases. Cox regression was used to test association with age at diagnosis. Individuals without neurologic disease were used to rule out confounding. Gene-level analysis and functional annotation were conducted using Functional Mapping and Annotation of GWAS platform (FUMA).
RESULTS
The GWAS revealed 2 linked but seemingly independent association signals that mapped to on chromosome 9. was significant in gene-based analysis ( = 1E-8). The top signal (rs17763929, hazard ratio [HR] = 1.88, = 5E-8) replicated in PAGE (HR = 1.87, = 0.01) but not in PAGE. The second signal (rs73656147) was robust with no evidence of heterogeneity (HR = 1.95, = 3E-6 in NGRC; HR = 2.14, = 1E-3 in PAGE + PAGE, and HR = 2.00, = 9E-9 in meta-analysis of NGRC + PAGE + PAGE). The associations were with age at diagnosis, not confounded by age in patients or in the general population. The PD-associated regions included variants with Combined Annotation Dependent Depletion (CADD) scores = 10-19 (top 1%-10% most deleterious mutations in the genome), a missense with predicted destabilizing effect on LPPR1, an expression quantitative trait locus (eQTL) for (false discovery rate [FDR] = 4E-4), and variants that overlap with enhancers in and interact with promoters of and 9 other brain-expressed genes (Hi-C FDR < 1E-6).
CONCLUSIONS
Through association with age at diagnosis, we uncovered as a modifier gene for PD. expression promotes neuronal regeneration after injury in animal models. Present data provide a strong foundation for mechanistic studies to test as a driver of response to damage and a therapeutic target for enhancing neuroregeneration and slowing disease progression.
目的
确定帕金森病（PD）诊断年龄的修饰因子。
方法
全基因组关联研究（GWAS）纳入了来自神经遗传学研究联盟（NGRC）研究的1950例PD患者。在帕金森病、基因与环境研究中进行了重复验证，该研究包括209例现患（PAGE）和517例新发（PAGE）PD病例。采用Cox回归检验与诊断年龄的关联。使用无神经系统疾病的个体来排除混杂因素。使用GWAS平台的功能映射和注释（FUMA）进行基因水平分析和功能注释。
结果
GWAS揭示了2个连锁但看似独立的关联信号，定位于9号染色体上。在基于基因的分析中具有显著性（=1E-8）。最强信号（rs17763929，风险比[HR]=1.88，=5E-8）在PAGE中得到重复验证（HR=1.87，=0.01），但在PAGE中未得到验证。第二个信号（rs73656147）很稳健，没有异质性证据（在NGRC中HR=1.95，=3E-6；在PAGE+PAGE中HR=2.14，=1E-3，在NGRC+PAGE+PAGE的荟萃分析中HR=2.00，=9E-9）。这些关联与诊断年龄相关，在患者或一般人群中不受年龄的混杂影响。与PD相关的区域包括综合注释依赖缺失（CADD）评分=10-19的变异（基因组中最有害的1%-10%的突变）、一个对LPPR1有预测的不稳定作用的错义突变、一个的表达数量性状位点（eQTL）（错误发现率[FDR]=4E-4），以及与和9个其他脑表达基因的启动子相互作用的增强子重叠的变异（Hi-C FDR<1E-6）。
结论
通过与诊断年龄的关联，我们发现作为PD的一个修饰基因。在动物模型中，的表达促进损伤后神经元再生。目前的数据为机制研究提供了坚实的基础，以检验作为损伤反应的驱动因素以及增强神经再生和减缓疾病进展的治疗靶点。
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