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 language | English |
|---|---|
| Journal | Alzheimer's and Dementia |
| Volume | 11 |
| Issue number | 12 |
| Pages (from-to) | 1407-1416 |
| Number of pages | 10 |
| ISSN | 1552-5260 |
| DOIs | |
| Publication status | Published - 01.12.2015 |
Funding
The authors are grateful to the individuals participating in this study. The authors thank Ms Brit-Maren Schjeide for excellent technical assistance. The authors thank Drs Thorlakur Jonsson and Kari Stefansson for providing us with data of the association analysis of TREM2 rs75932628 and PD in the Icelandic population beyond those provided in the original publication [15] . The authors thank Dr. Owen A. Ross for providing us with the IDs of the Coriell samples genotyped in the original publication [12] . Competing interests: None of the authors reports any disclosures. Funding: This project was funded by grants from the German Ministry for Education and Research ( BMBF , grant 16SV5538 to L.B., grant 01UW0808 to U.L., and E.S.-T.), the Cure Alzheimer's Fund and Michael J. Fox Foundation (to L.B.), the Innovation Fund of the Max Planck Society ( M.FE.A.BILD0002 to U.L.), the Katharina-Hardt-Stiftung , Bad Homburg, Germany, the AXA Research Fund , the Fondation Université Pierre et Marie Curie and the Fondation pour la Recherche sur Alzheimer , Paris, France (to HH), the MND Association UK (to KEM, PS, AAC), the Research Council of Norway and the South-Eastern Norway Regional Health Authority (to M.T.), the NIEHS of the National Institutes of Health ( R01ES013717 to B.R.). Sample collection in Linköping was funded by the European Union as part of the Fifth Framework program (project number QLK4-CT-1999-01133 to N.D.). The research leading to these results has received funding from the program “Investissements d'avenir” ANR-10-IAIHU-06.
