The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

Christina M. Lill, Aina Rengmark, Lasse Pihlstrøm, Isabella Fogh, Aleksey Shatunov, Patrick M. Sleiman, Li San Wang, Tian Liu, Christina F. Lassen, Esther Meissner, Panos Alexopoulos, Andrea Calvo, Adriano Chio, Nil Dizdar, Frank Faltraco, Lars Forsgren, Julia Kirchheiner, Alexander Kurz, Jan P. Larsen, Maria LiebschJan Linder, Karen E. Morrison, Hans Nissbrandt, Markus Otto, Jens Pahnke, Amanda Partch, Gabriella Restagno, Dan Rujescu, Cathrin Schnack, Christopher E. Shaw, Pamela J. Shaw, Hayrettin Tumani, Ole Bjørn Tysnes, Otto Valladares, Vincenzo Silani, Leonard H. Van Den Berg, Wouter Van Rheenen, Jan H. Veldink, Ulman Lindenberger, Elisabeth Steinhagen-Thiessen, Stefan Teipel, Robert Perneczky, Hakon Hakonarson, Harald Hampel, Christine A F Von Arnim, Jørgen H. Olsen, Vivianna M. Van Deerlin, Ammar Al-Chalabi, Mathias Toft, Beate Ritz, Lars Bertram

Research output: Contribution to journalArticle

Abstract

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10-25). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.

Original languageEnglish
Pages (from-to)1407-1416
Number of pages10
JournalAlzheimer's and Dementia
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 1 2015

Keywords

  • Alzheimer disease
  • Amyotrophic lateral sclerosis
  • Frontotemporal lobar degeneration
  • Genetic association
  • GWAS
  • Imputation
  • Meta-analysis
  • Neurodegenerative disease
  • Parkinson disease
  • R47H
  • Rare variant
  • rs75932628
  • TREM2

ASJC Scopus subject areas

  • Clinical Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Epidemiology
  • Health Policy

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  • Cite this

    Lill, C. M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P. M., Wang, L. S., Liu, T., Lassen, C. F., Meissner, E., Alexopoulos, P., Calvo, A., Chio, A., Dizdar, N., Faltraco, F., Forsgren, L., Kirchheiner, J., Kurz, A., Larsen, J. P., ... Bertram, L. (2015). The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease. Alzheimer's and Dementia, 11(12), 1407-1416. https://doi.org/10.1016/j.jalz.2014.12.009