Journal
NEUROBIOLOGY OF AGING
Volume 35, Issue 3, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2013.09.009
Keywords
TREM2; Alzheimer's disease; Frontotemporal dementia; Rare variants; Meta-analysis; IgV-set domain
Categories
Funding
- Inter-university Attraction Poles program of the Belgian Science Policy Office (BELSPO)
- Foundation for Alzheimer Research (SAO-FRA)
- Queen Elisabeth Medical Foundation (QEMF)
- Methusalem Excellence Program of the Flemish Government (EWI)
- Research Foundation Flanders (FWO)
- Agency for Innovation by Science and Technology Flanders (IWT)
- University Research Fund (UA)
- Medical Research Foundation Antwerp, Belgium
- MetLife Foundation Award
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Homozygous mutations in exon 2 of TREM2, a gene involved in Nasu-Hakola disease, can cause frontotemporal dementia (FTD). Moreover, a rare TREM2 exon 2 variant (p.R47H) was reported to increase the risk of Alzheimer's disease (AD) with an odds ratio as strong as that for APOE epsilon 4. We systematically screened the TREM2 coding region within a Belgian study on neurodegenerative brain diseases (1216 AD patients, 357 FTD patients, and 1094 controls). We observed an enrichment of rare variants across TREM2 in both AD and FTD patients compared to controls, most notably in the extracellular IgV-set domain (relative risk = 3.84 [95% confidence interval = 1.29-11.44]; p = 0.009 for AD; relative risk = 6.19 [95% confidence interval = 1.86-20.61]; p = 0.0007 for FTD). None of the rare variants individually reached significant association, but the frequency of p.R47H was increased similar to 3-fold in both AD and FTD patients compared to controls, in line with previous reports. Meta-analysis including 11 previously screened AD cohorts confirmed the association of p.R47H with AD (p = 2.93 x 10(-17)). Our data corroborate and extend previous findings to include an increased frequency of rare heterozygous TREM2 variations in AD and FTD, and show that TREM2 variants may play a role in neurodegenerative diseases in general. (C) 2014 Elsevier Inc. All rights reserved.
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