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

71 Citations (Scopus)

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
JournalNeurobiology of Aging
Volume35
Issue number6
DOIs
StatePublished - Jun 1 2014

Fingerprint

Alzheimer Disease
Cerebrospinal Fluid
Meta-Analysis
Biomarkers
Genes
Exome
Genome-Wide Association Study
Single Nucleotide Polymorphism
Chromosomes
Proteins

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

Cite this

Benitez, B. A., Jin, S. C., Guerreiro, R., Graham, R., Lord, J., Harold, D., ... Cruchaga, C. (2014). Missense variant in TREML2 protects against Alzheimer's disease. Neurobiology of Aging, 35(6). https://doi.org/10.1016/j.neurobiolaging.2013.12.010

Missense variant in TREML2 protects against Alzheimer's disease. / Benitez, Bruno A.; Jin, Sheng Chih; Guerreiro, Rita; Graham, Rob; Lord, Jenny; Harold, Denise; Sims, Rebecca; Lambert, Jean Charles; Gibbs, J. Raphael; Bras, Jose; Sassi, Celeste; Harari, Oscar; Bertelsen, Sarah; Lupton, Michelle K.; Powell, John; Bellenguez, Celine; Brown, Kristelle; Medway, Christopher; Haddick, Patrick C G; Van der Brug, Marcel P.; Bhangale, Tushar; Ortmann, Ward; Behrens, Tim; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A.; Schellenberg, Gerard D.; Haines, Jonathan L.; Turton, Jim; Braae, Anne; Barber, Imelda; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Williams, Julie; Kauwe, John S K; Amouyel, Philippe; Morgan, Kevin; Singleton, Andy; Hardy, John; Goate, Alison M.; Cruchaga, Carlos.

In: Neurobiology of Aging, Vol. 35, No. 6, 01.06.2014.

Research output: Contribution to journalArticle

Benitez, BA, Jin, SC, Guerreiro, R, Graham, R, Lord, J, Harold, D, Sims, R, Lambert, JC, Gibbs, JR, 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, Schellenberg, GD, 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 2014, 'Missense variant in TREML2 protects against Alzheimer's disease', Neurobiology of Aging, vol. 35, no. 6. https://doi.org/10.1016/j.neurobiolaging.2013.12.010
Benitez, Bruno A. ; Jin, Sheng Chih ; Guerreiro, Rita ; Graham, Rob ; Lord, Jenny ; Harold, Denise ; Sims, Rebecca ; Lambert, Jean Charles ; Gibbs, J. Raphael ; Bras, Jose ; Sassi, Celeste ; Harari, Oscar ; Bertelsen, Sarah ; Lupton, Michelle K. ; Powell, John ; Bellenguez, Celine ; Brown, Kristelle ; Medway, Christopher ; Haddick, Patrick C G ; Van der Brug, Marcel P. ; Bhangale, Tushar ; Ortmann, Ward ; Behrens, Tim ; Mayeux, Richard ; Pericak-Vance, Margaret A ; Farrer, Lindsay A. ; Schellenberg, Gerard D. ; Haines, Jonathan L. ; Turton, Jim ; Braae, Anne ; Barber, Imelda ; Fagan, Anne M. ; Holtzman, David M. ; Morris, John C. ; Williams, Julie ; Kauwe, John S K ; Amouyel, Philippe ; Morgan, Kevin ; Singleton, Andy ; Hardy, John ; Goate, Alison M. ; Cruchaga, Carlos. / Missense variant in TREML2 protects against Alzheimer's disease. In: Neurobiology of Aging. 2014 ; Vol. 35, No. 6.
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AU - Benitez, Bruno A.

AU - Jin, Sheng Chih

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AU - Graham, Rob

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AU - Harold, Denise

AU - Sims, Rebecca

AU - Lambert, Jean Charles

AU - Gibbs, J. Raphael

AU - Bras, Jose

AU - Sassi, Celeste

AU - Harari, Oscar

AU - Bertelsen, Sarah

AU - Lupton, Michelle K.

AU - Powell, John

AU - Bellenguez, Celine

AU - Brown, Kristelle

AU - Medway, Christopher

AU - Haddick, Patrick C G

AU - Van der Brug, Marcel P.

AU - Bhangale, Tushar

AU - Ortmann, Ward

AU - Behrens, Tim

AU - Mayeux, Richard

AU - Pericak-Vance, Margaret A

AU - Farrer, Lindsay A.

AU - Schellenberg, Gerard D.

AU - Haines, Jonathan L.

AU - Turton, Jim

AU - Braae, Anne

AU - Barber, Imelda

AU - Fagan, Anne M.

AU - Holtzman, David M.

AU - Morris, John C.

AU - Williams, Julie

AU - Kauwe, John S K

AU - Amouyel, Philippe

AU - Morgan, Kevin

AU - Singleton, Andy

AU - Hardy, John

AU - Goate, Alison M.

AU - Cruchaga, Carlos

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