The role of TREM2 R47H as a risk factor for Alzheimers disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinsons disease
2015 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 12, 1407-1416 p.Article in journal (Refereed) PublishedText
A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimers disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinsons 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 (Ab42) 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 x 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 5 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR 5 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 Ab42 suggesting that TREM2s role in AD may involve tau dysfunction. (C) 2015 The Alzheimers Association. Published by Elsevier Inc. All rights reserved.
Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC , 2015. Vol. 11, no 12, 1407-1416 p.
Neurodegenerative disease; Alzheimer disease; Frontotemporal lobar degeneration; Amyotrophic lateral sclerosis; Parkinson disease; TREM2; R47H; rs75932628; Rare variant; Genetic association; GWAS; Imputation; Meta-analysis
IdentifiersURN: urn:nbn:se:liu:diva-123758DOI: 10.1016/j.jalz.2014.12.009ISI: 000366721600002PubMedID: 25936935OAI: oai:DiVA.org:liu-123758DiVA: diva2:892973
Funding Agencies|German Ministry for Education and Research (BMBF) [16SV5538, 01UW0808]; Cure Alzheimers Fund; Michael J. Fox Foundation; Innovation Fund of the Max Planck Society [M.FE.A.BILD0002]; Katharina-Hardt-Stiftung, Bad Homburg, Germany; AXA Research Fund; Fondation Universite Pierre et Marie Curie; Fondation pour la Recherche sur Alzheimer, Paris, France; MND Association UK; Research Council of Norway; South-Eastern Norway Regional Health Authority; NIEHS of the National Institutes of Health [R01ES013717]; European Union [QLK4-CT-1999-01133]; program "Investissements davenir" [ANR-10-IAIHU-06]2016-01-112016-01-112016-04-25