Missense variant in TREML2 protects against Alzheimer's disease

Bruno A. Benitez, Sheng Chih Jin, Rita Guerreiro, Rob Graham, Jenny Lord, Denise Harold, Rebecca Sims, Jean Charles Lambert, J. Raphael Gibbs, Jose Bras, Celeste Sassi, Oscar Harari, Sarah Bertelsen, Michelle K. Lupton, John Powell, Celine Bellenguez, Kristelle Brown, Christopher Medway, Patrick C.G. Haddick, Marcel P. Van der BrugTushar Bhangale, Ward Ortmann, Tim Behrens, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Jim Turton, Anne Braae, Imelda Barber, Anne M. Fagan, David M. Holtzman, John C. Morris, Julie Williams, John S.K. Kauwe, Philippe Amouyel, Kevin Morgan, Andy Singleton, John Hardy, Alison M. Goate, Carlos Cruchaga

Research output: Contribution to journalArticle

72 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1510.e19-1510.e26
JournalNeurobiology of aging
Volume35
Issue number6
DOIs
StatePublished - Jun 2014

Keywords

  • Alzheimer's disease
  • Association
  • Conditional analysis
  • Endophenotype
  • Gene
  • Genome-wide association studies
  • TREM2

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

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  • Cite this

    Benitez, B. A., Jin, S. C., Guerreiro, R., Graham, R., Lord, J., Harold, D., Sims, R., Lambert, J. C., Gibbs, J. R., Bras, J., Sassi, C., Harari, O., Bertelsen, S., Lupton, M. K., Powell, J., Bellenguez, C., Brown, K., Medway, C., Haddick, P. C. G., ... Cruchaga, C. (2014). Missense variant in TREML2 protects against Alzheimer's disease. Neurobiology of aging, 35(6), 1510.e19-1510.e26. https://doi.org/10.1016/j.neurobiolaging.2013.12.010