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

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102 Scopus citations


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
Pages (from-to)1510.e19-1510.e26
JournalNeurobiology of Aging
Issue number6
StatePublished - Jun 2014


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


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