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Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson’s Disease Susceptibility

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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.

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Acknowledgments

This work was supported by funding from the National Nature Science Foundation of China (Grant No. 81300945 and 81471294).

Conflict of interest

The authors reported no potential conflicts of interest.

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Author notes

    Authors and Affiliations

    1. Genome Analysis Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Xiqi Dao 32, Tianjin Airport Economic Area, Tianjin, 300308, China

      Guiyou Liu

    2. Department of Neurology, The First Hospital of Harbin, Harbin, China

      Yongquan Liu & Jiafeng Liu

    3. School of Life Science and Technology, Harbin Institute of Technology, Harbin, China

      Qinghua Jiang

    4. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China

      Yongshuai Jiang

    5. Department of Nutrition and Food Hygiene, School of Public Health,, Harbin Medical University, Harbin, China

      Rennan Feng

    6. Department of Statistics, Rice University, Houston, TX, USA

      Liangcai Zhang

    7. Department of Human Genetics, University of California at Los Angeles, Los Angeles, CA, USA

      Zugen Chen

    8. Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China

      Keshen Li

    9. Stroke Center, Neurology & Neurosurgery Division, The Clinical Medicine Research Institute & The First Affiliated Hospital, Jinan University Guangzhou, Guangzhou, China

      Keshen Li

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    1. Guiyou Liu
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    Correspondence to Keshen Li or Jiafeng Liu.

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    Guiyou Liu and Yongquan Liu contributed equally to this work.

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    Liu, G., Liu, Y., Jiang, Q. et al. Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson’s Disease Susceptibility. Mol Neurobiol 53, 4931–4938 (2016). https://doi.org/10.1007/s12035-015-9416-7

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    • DOI: https://doi.org/10.1007/s12035-015-9416-7

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