Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson's Disease Susceptibility
Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson's Disease Susceptibility
复制标题
趋同的遗传和表达数据集强调 TREM2 在帕金森病易感性中的作用
DOI：
10.1007/s12035-015-9416-7
复制
发表时间：
2016-09-01
影响因子：
5.1
通讯作者：
Liu, Jiafeng
中科院分区：
文献类型：
--
作者：
Liu, Guiyou;Liu, Yongquan;Liu, Jiafeng
据报道，一种罕见的TREM2错义突变（rs75932628-T）可导致显著的阿尔茨海默病（AD）风险。最近的一项研究表明，没有证据表明这种变异与帕金森病（PD）有关。在这里，我们使用遗传和表达数据重新研究TREM2与PD易感性之间的潜在关联。在第一阶段，使用10项独立研究（N = 89,157； 8787例和80,370例对照），我们进行了亚组荟萃分析。在无北欧亚组中，我们发现rs75932628与PD之间存在显著相关性(P = 3.10E-03，比值比（OR) = 3.88, 95%可信区间（CI） 1.58-9.54），无北欧亚组的PD风险显著高于北欧亚组（Mann-Whitney检验P = 0.01）。在第二阶段，我们使用了一项大规模PD全基因组关联研究（GWAS; N = 108,990; 13,708例和95,282例对照）的总结结果来寻找其他TREM2变异对PD易感性的影响。我们在TREM2的上游和下游50 kb范围内发现了14个与PD相关的单核苷酸多态性（snp）。在第三阶段，使用两个脑表达GWAS数据集（N = 773），我们确定了14个SNPs中的6个调节TREM2表达增加。在第4阶段，利用全人类基因组微阵列数据（N = 50），我们进一步发现，与对照组相比，PD患者前额叶皮层中TREM2的表达显著增加。综上所述，趋同的遗传和表达数据集表明，TREM2是PD的一个潜在危险因素，可能是PD和其他神经退行性疾病的治疗靶点。
A rare TREM2 missense mutation (rs75932628-T) was reported to confer a significant Alzheimer's disease (AD) risk. A recent study indicated no evidence of the involvement of this variant in Parkinson's disease (PD). Here, we used the genetic and expression data to reinvestigate the potential association between TREM2 and PD susceptibility. In stage 1, using 10 independent studies (N = 89,157; 8787 cases and 80,370 controls), we conducted a subgroup meta-analysis. We identified a significant association between rs75932628 and PD (P = 3.10E-03, odds ratio (OR) = 3.88, 95 % confidence interval (CI) 1.58-9.54) in No-Northern Europe subgroup, and significantly increased PD risks (P = 0.01 for Mann-Whitney test) in No-Northern Europe subgroup than in Northern Europe subgroup. In stage 2, we used the summary results from a large-scale PD genome-wide association study (GWAS; N = 108,990; 13,708 cases and 95,282 controls) to search for other TREM2 variants contributing to PD susceptibility. We identified 14 single-nucleotide polymorphisms (SNPs) associated with PD within 50-kb upstream and downstream range of TREM2. In stage 3, using two brain expression GWAS datasets (N = 773), we identified 6 of the 14 SNPs regulating increased expression of TREM2. In stage 4, using the whole human genome microarray data (N = 50), we further identified significantly increased expression of TREM2 in PD cases compared with controls in human prefrontal cortex. In summary, convergent genetic and expression datasets demonstrate that TREM2 is a potent risk factor for PD and may be a therapeutic target in PD and other neurodegenerative diseases.