title: Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson's Disease Susceptibility.
abstract: 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.
authors.affiliation: Genome Analysis Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Xiqi Dao 32, Tianjin Airport Economic Area, Tianjin, 300308, China.
authors.forename: Guiyou
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Neurology, The First Hospital of Harbin, Harbin, China.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
authors.forename: Yongshuai
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health,, Harbin Medical University, Harbin, China.
authors.forename: Rennan
authors.initials: R
authors.lastname: Feng
authors.affiliation: Department of Statistics, Rice University, Houston, TX, USA.
authors.forename: Liangcai
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Zugen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China. keshenli2012@163.com.|Stroke Center, Neurology & Neurosurgery Division, The Clinical Medicine Research Institute & The First Affiliated Hospital, Jinan University Guangzhou, Guangzhou, China. keshenli2012@163.com.
authors.forename: Keshen
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Neurology, The First Hospital of Harbin, Harbin, China. ljf@nefu.edu.cn.
authors.forename: Jiafeng
authors.initials: J
authors.lastname: Liu
mesh_terms: D016022:Case-Control Studies; D030541:Databases, Genetic; D005060:Europe / Q000453:epidemiology; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics*; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer’s disease; Genome-wide association study; Parkinson’s disease; TREM2; rs75932628