Missense variant in TREML2 protects against Alzheimer's disease.

TitleMissense variant in TREML2 protects against Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsBenitez BA, Jin SChih, Guerreiro R, Graham R, Lord J, Harold D, Sims R, Lambert J-C, J Gibbs R, Bras J, Sassi C, Harari O, Bertelsen S, Lupton MK, Powell J, Bellenguez C, Brown K, Medway C, Haddick PCG, van der Brug MP, Bhangale T, Ortmann W, Behrens T, Mayeux R, Pericak-Vance MA, Farrer LA, Gerard D Schellenberg, Haines JL, Turton J, Braae A, Barber I, Fagan AM, Holtzman DM, Morris JC, Williams J, Kauwe JSK, Amouyel P, Morgan K, Singleton A, Hardy J, Goate AM, Cruchaga C
Corporate Authors3C Study Group, EADI consortium, Alzheimer's Disease Genetic Consortium(ADGC), Alzheimer's Disease Neuroimaging Initiative(ADNI), GERAD Consortium
JournalNeurobiol Aging
Volume35
Issue6
Pagination1510.e19-26
Date Published2014 Jun
ISSN1558-1497
Abstract

TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.

DOI10.1016/j.neurobiolaging.2013.12.010
Alternate JournalNeurobiol. Aging
PubMed ID24439484
PubMed Central IDPMC3961557
Grant List089698 / / Wellcome Trust / United Kingdom
AG010124 / AG / NIA NIH HHS / United States
AG05136 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
P01-AG026276 / AG / NIA NIH HHS / United States
P01-AG03991 / AG / NIA NIH HHS / United States
P01-AG05131 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P30 NS069329 / NS / NINDS NIH HHS / United States
P30-NS069329E01 / NS / NINDS NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P50-AG05681 / AG / NIA NIH HHS / United States
R01 AG016208 / AG / NIA NIH HHS / United States
R01 AG035083 / AG / NIA NIH HHS / United States
R01 AG042611 / AG / NIA NIH HHS / United States
R01 AG044546 / AG / NIA NIH HHS / United States
R01-AG035083 / AG / NIA NIH HHS / United States
R01-AG042611 / AG / NIA NIH HHS / United States
R01-AG044546 / AG / NIA NIH HHS / United States
R01-AG16208 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01-AG032984 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom