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 Brug; Tushar 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

doi:10.1016/j.neurobiolaging.2013.12.010

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 journal › Article › peer-review

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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 language	English
Pages (from-to)	1510.e19-1510.e26
Journal	Neurobiology of Aging
Volume	35
Issue number	6
DOIs	https://doi.org/10.1016/j.neurobiolaging.2013.12.010
State	Published - Jun 2014

Keywords

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

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10.1016/j.neurobiolaging.2013.12.010

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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

@article{de705ec1d5d0492e8fb66007d2f5900a,

title = "Missense variant in TREML2 protects against Alzheimer's disease",

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.",

keywords = "Alzheimer's disease, Association, Conditional analysis, Endophenotype, Gene, Genome-wide association studies, TREM2",

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

note = "Funding Information: The authors thank the ARUK consortium for collection of the samples used, and the patients and families whose participation made this work possible. The authors also thank ARUK and the Big Lottery Fund for financial support of this work, and ARUK for funding the PhD studentship of Jenny Lord. Funding Information: EADI1 was supported by the French National Foundation on Alzheimer's disease and related disorders. Data management involved the Centre National de G{\'e}notypage, the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau), and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease). The Three-City Study was performed as part of collaboration between the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (Inserm), the Victor Segalen Bordeaux II University, and Sanofi-Synth{\'e}labo. The Fondation pour la Recherche M{\'e}dicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salari{\'e}s , Direction G{\'e}n{\'e}rale de la Sant{\'e} , MGEN , Institut de la Long{\'e}vit{\'e} , Agence Fran{\c c}aise de S{\'e}curit{\'e} Sanitaire des Produits de Sant{\'e} , the Aquitaine and Bourgogne Regional Councils , Fondation de France , and the joint French Ministry of Research and INSERM “Cohortes et collections de donn{\'e}es biologiques” programme . Lille G{\'e}nop{\^o}le received an unconditional grant from Eisai . Funding Information: This work was supported by grants from National Institutes of Health ( P30-NS069329–01 , R01-AG044546 , R01-AG035083 , R01-AG16208 , P50-AG05681 , P01-AG03991 , P01-AG026276 , AG05136 , and PO1-AG05131 , U01-AG032984 , AG010124 , R01-AG042611 ), the Alzheimer Association (NIRG-11–200110), and the Barnes-Jewish Hospital Foundation . This research was conducted while Carlos Cruchaga was a recipient of a New Investigator Award in Alzheimer's disease from the American Federation for Aging Research. CC is a recipient of a BrightFocus Foundation Alzheimer's Disease Research Grant ( A2013359S ). The authors thank the Clinical and Genetics Cores of the Knight ADRC at Washington University for clinical and cognitive assessments of the participants and for APOE genotypes and the Biomarker Core of the Adult Children Study at Washington University for the cerebrospinal fluid collection and ptau assays. Funding Information: This study incorporated imputed summary results from the genetic and environmental risk for Alzheimer's disease (GERAD1) genome-wide association study. GERAD acknowledgements: Cardiff University was supported by the Wellcome Trust , Medical Research Council (MRC) , Alzheimer's Research UK (ARUK) , and the Welsh Assembly Government . ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester, and Belfast. The Belfast group acknowledges support from the Alzheimer's Society , Ulster Garden Villages , Northern Ireland R&D Office , and the Royal College of Physicians and Dunhill Medical Trust . The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the Oxford Project to Investigate Memory and Ageing group. Washington University was funded by National Institutes of Health grants, Barnes Jewish Foundation, and the Charles and Joanne Knight Alzheimer's Research Initiative . Patient recruitment for the MRC Prion Unit and UCL Department of Neurodegenerative Disease collection was supported by the UCLH and UCL Biomedical Centre . London and the South East Region AD project was funded by Lundbeck SA . The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF) , Competence Network Dementia and Competence Network Degenerative Dementia , and by the Alfried Krupp von Bohlen und Halbach-Stiftung . The GERAD Consortium also used samples ascertained by the National Institute of Mental Health AD Genetics Initiative. Funding Information: The KORA F4 studies were financed by Helmholtz Zentrum M{\"u}nchen , German Research Center for Environmental Health , BMBF , German National Genome Research Network , and the Munich Center of Health Sciences . The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr jur. G.Schmidt, Chairman) and BMBF . Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging . The authors acknowledge the use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases , National Institute of Allergy and Infectious Diseases , National Human Genome Research Institute , National Institute of Child Health and Human Development , and Juvenile Diabetes Research Foundation International . ",

year = "2014",

month = jun,

doi = "10.1016/j.neurobiolaging.2013.12.010",

language = "English",

volume = "35",

pages = "1510.e19--1510.e26",

journal = "Neurobiology of Aging",

issn = "0197-4580",

number = "6",

}

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, pp. 1510.e19-1510.e26. https://doi.org/10.1016/j.neurobiolaging.2013.12.010

TY - JOUR

T1 - Missense variant in TREML2 protects against Alzheimer's disease

AU - Benitez, Bruno A.

AU - Jin, Sheng Chih

AU - Guerreiro, Rita

AU - Graham, Rob

AU - Lord, Jenny

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

N1 - Funding Information: The authors thank the ARUK consortium for collection of the samples used, and the patients and families whose participation made this work possible. The authors also thank ARUK and the Big Lottery Fund for financial support of this work, and ARUK for funding the PhD studentship of Jenny Lord. Funding Information: EADI1 was supported by the French National Foundation on Alzheimer's disease and related disorders. Data management involved the Centre National de Génotypage, the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau), and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease). The Three-City Study was performed as part of collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University, and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés , Direction Générale de la Santé , MGEN , Institut de la Longévité , Agence Française de Sécurité Sanitaire des Produits de Santé , the Aquitaine and Bourgogne Regional Councils , Fondation de France , and the joint French Ministry of Research and INSERM “Cohortes et collections de données biologiques” programme . Lille Génopôle received an unconditional grant from Eisai . Funding Information: This work was supported by grants from National Institutes of Health ( P30-NS069329–01 , R01-AG044546 , R01-AG035083 , R01-AG16208 , P50-AG05681 , P01-AG03991 , P01-AG026276 , AG05136 , and PO1-AG05131 , U01-AG032984 , AG010124 , R01-AG042611 ), the Alzheimer Association (NIRG-11–200110), and the Barnes-Jewish Hospital Foundation . This research was conducted while Carlos Cruchaga was a recipient of a New Investigator Award in Alzheimer's disease from the American Federation for Aging Research. CC is a recipient of a BrightFocus Foundation Alzheimer's Disease Research Grant ( A2013359S ). The authors thank the Clinical and Genetics Cores of the Knight ADRC at Washington University for clinical and cognitive assessments of the participants and for APOE genotypes and the Biomarker Core of the Adult Children Study at Washington University for the cerebrospinal fluid collection and ptau assays. Funding Information: This study incorporated imputed summary results from the genetic and environmental risk for Alzheimer's disease (GERAD1) genome-wide association study. GERAD acknowledgements: Cardiff University was supported by the Wellcome Trust , Medical Research Council (MRC) , Alzheimer's Research UK (ARUK) , and the Welsh Assembly Government . ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester, and Belfast. The Belfast group acknowledges support from the Alzheimer's Society , Ulster Garden Villages , Northern Ireland R&D Office , and the Royal College of Physicians and Dunhill Medical Trust . The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the Oxford Project to Investigate Memory and Ageing group. Washington University was funded by National Institutes of Health grants, Barnes Jewish Foundation, and the Charles and Joanne Knight Alzheimer's Research Initiative . Patient recruitment for the MRC Prion Unit and UCL Department of Neurodegenerative Disease collection was supported by the UCLH and UCL Biomedical Centre . London and the South East Region AD project was funded by Lundbeck SA . The Bonn group was supported by the German Federal Ministry of Education and Research (BMBF) , Competence Network Dementia and Competence Network Degenerative Dementia , and by the Alfried Krupp von Bohlen und Halbach-Stiftung . The GERAD Consortium also used samples ascertained by the National Institute of Mental Health AD Genetics Initiative. Funding Information: The KORA F4 studies were financed by Helmholtz Zentrum München , German Research Center for Environmental Health , BMBF , German National Genome Research Network , and the Munich Center of Health Sciences . The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr jur. G.Schmidt, Chairman) and BMBF . Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging . The authors acknowledge the use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases , National Institute of Allergy and Infectious Diseases , National Human Genome Research Institute , National Institute of Child Health and Human Development , and Juvenile Diabetes Research Foundation International .

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Association

KW - Conditional analysis

KW - Endophenotype

KW - Gene

KW - Genome-wide association studies

KW - TREM2

UR - http://www.scopus.com/inward/record.url?scp=84903366979&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2013.12.010

DO - 10.1016/j.neurobiolaging.2013.12.010

M3 - Article

C2 - 24439484

AN - SCOPUS:84903366979

SN - 0197-4580

VL - 35

SP - 1510.e19-1510.e26

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 6

ER -

Missense variant in TREML2 protects against Alzheimer's disease

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