Abstract
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 '4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 '8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
| Original language | English |
|---|---|
| Pages (from-to) | 1373-1384 |
| Number of pages | 12 |
| Journal | Nature Genetics |
| Volume | 49 |
| Issue number | 9 |
| DOIs | |
| State | Published - 1 Sep 2017 |
| Externally published | Yes |
Access to Document
Fingerprint
Dive into the research topics of 'Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature Genetics, Vol. 49, No. 9, 01.09.2017, p. 1373-1384.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
AU - Sims, Rebecca
AU - Van Der Lee, Sven J.
AU - Naj, Adam C.
AU - Bellenguez, Céline
AU - Badarinarayan, Nandini
AU - Jakobsdottir, Johanna
AU - Kunkle, Brian W.
AU - Boland, Anne
AU - Raybould, Rachel
AU - Bis, Joshua C.
AU - Martin, Eden R.
AU - Grenier-Boley, Benjamin
AU - Heilmann-Heimbach, Stefanie
AU - Chouraki, Vincent
AU - Kuzma, Amanda B.
AU - Sleegers, Kristel
AU - Vronskaya, Maria
AU - Ruiz, Agustin
AU - Graham, Robert R.
AU - Olaso, Robert
AU - Hoffmann, Per
AU - Grove, Megan L.
AU - Vardarajan, Badri N.
AU - Hiltunen, Mikko
AU - Nöthen, Markus M.
AU - White, Charles C.
AU - Hamilton-Nelson, Kara L.
AU - Epelbaum, Jacques
AU - Maier, Wolfgang
AU - Choi, Seung Hoan
AU - Beecham, Gary W.
AU - Dulary, Cécile
AU - Herms, Stefan
AU - Smith, Albert V.
AU - Funk, Cory C.
AU - Derbois, Céline
AU - Forstner, Andreas J.
AU - Ahmad, Shahzad
AU - Li, Hongdong
AU - Bacq, Delphine
AU - Harold, Denise
AU - Satizabal, Claudia L.
AU - Valladares, Otto
AU - Squassina, Alessio
AU - Thomas, Rhodri
AU - Brody, Jennifer A.
AU - Qu, Liming
AU - Sánchez-Juan, Pascual
AU - Morgan, Taniesha
AU - Wolters, Frank J.
AU - Zhao, Yi
AU - Garcia, Florentino Sanchez
AU - Denning, Nicola
AU - Fornage, Myriam
AU - Malamon, John
AU - Naranjo, Maria Candida Deniz
AU - Majounie, Elisa
AU - Mosley, Thomas H.
AU - Dombroski, Beth
AU - Wallon, David
AU - Lupton, Michelle K.
AU - Dupuis, Josée
AU - Whitehead, Patrice
AU - Fratiglioni, Laura
AU - Medway, Christopher
AU - Jian, Xueqiu
AU - Mukherjee, Shubhabrata
AU - Keller, Lina
AU - Brown, Kristelle
AU - Lin, Honghuang
AU - Cantwell, Laura B.
AU - Panza, Francesco
AU - McGuinness, Bernadette
AU - Moreno-Grau, Sonia
AU - Burgess, Jeremy D.
AU - Solfrizzi, Vincenzo
AU - Proitsi, Petra
AU - Adams, Hieab H.
AU - Allen, Mariet
AU - Seripa, Davide
AU - Pastor, Pau
AU - Cupples, L. Adrienne
AU - Price, Nathan D.
AU - Hannequin, Didier
AU - Frank-García, Ana
AU - Levy, Daniel
AU - Chakrabarty, Paramita
AU - Caffarra, Paolo
AU - Giegling, Ina
AU - Beiser, Alexa S.
AU - Giedraitis, Vilmantas
AU - Hampel, Harald
AU - Garcia, Melissa E.
AU - Wang, Xue
AU - Lannfelt, Lars
AU - Mecocci, Patrizia
AU - Eiriksdottir, Gudny
AU - Crane, Paul K.
AU - Pasquier, Florence
AU - Boccardi, Virginia
AU - Henández, Isabel
AU - Barber, Robert C.
AU - Scherer, Martin
AU - Tarraga, Lluis
AU - Adams, Perrie M.
AU - Leber, Markus
AU - Chen, Yuning
AU - Albert, Marilyn S.
AU - Riedel-Heller, Steffi
AU - Emilsson, Valur
AU - Beekly, Duane
AU - Braae, Anne
AU - Schmidt, Reinhold
AU - Blacker, Deborah
AU - Masullo, Carlo
AU - Schmidt, Helena
AU - Doody, Rachelle S.
AU - Spalletta, Gianfranco
AU - Longstreth, W. T.
AU - Fairchild, Thomas J.
AU - Bossù, Paola
AU - Lopez, Oscar L.
AU - Frosch, Matthew P.
AU - Sacchinelli, Eleonora
AU - Ghetti, Bernardino
AU - Yang, Qiong
AU - Huebinger, Ryan M.
AU - Jessen, Frank
AU - Li, Shuo
AU - Kamboh, M. Ilyas
AU - Morris, John C.
AU - Sotolongo-Grau, Oscar
AU - Katz, Mindy J.
AU - Corcoran, Chris
AU - Dunstan, Melanie
AU - Braddel, Amy
AU - Thomas, Charlene
AU - Meggy, Alun
AU - Marshall, Rachel
AU - Gerrish, Amy
AU - Chapman, Jade
AU - Aguilar, Miquel
AU - Taylor, Sarah
AU - Hill, Matt
AU - Fairén, Mònica Díez
AU - Hodges, Angela
AU - Vellas, Bruno
AU - Soininen, Hilkka
AU - Kloszewska, Iwona
AU - Daniilidou, Makrina
AU - Uphill, James
AU - Patel, Yogen
AU - Hughes, Joseph T.
AU - Lord, Jenny
AU - Turton, James
AU - Hartmann, Annette M.
AU - Cecchetti, Roberta
AU - Fenoglio, Chiara
AU - Serpente, Maria
AU - Arcaro, Marina
AU - Caltagirone, Carlo
AU - Orfei, Maria Donata
AU - Ciaramella, Antonio
AU - Pichler, Sabrina
AU - Mayhaus, Manuel
AU - Gu, Wei
AU - Lleó, Alberto
AU - Fortea, Juan
AU - Blesa, Rafael
AU - Barber, Imelda S.
AU - Brookes, Keeley
AU - Cupidi, Chiara
AU - Maletta, Raffaele Giovanni
AU - Carrell, David
AU - Sorbi, Sandro
AU - Moebus, Susanne
AU - Urbano, Maria
AU - Pilotto, Alberto
AU - Kornhuber, Johannes
AU - Bosco, Paolo
AU - Todd, Stephen
AU - Craig, David
AU - Johnston, Janet
AU - Gill, Michael
AU - Lawlor, Brian
AU - Lynch, Aoibhinn
AU - Fox, Nick C.
AU - Hardy, John
AU - Albin, Roger L.
AU - Apostolova, Liana G.
AU - Arnold, Steven E.
AU - Asthana, Sanjay
AU - Atwood, Craig S.
AU - Baldwin, Clinton T.
AU - Barnes, Lisa L.
AU - Barral, Sandra
AU - Beach, Thomas G.
AU - Becker, James T.
AU - Bigio, Eileen H.
AU - Bird, Thomas D.
AU - Boeve, Bradley F.
AU - Bowen, James D.
AU - Boxer, Adam
AU - Burke, James R.
AU - Burns, Jeffrey M.
AU - Buxbaum, Joseph D.
AU - Cairns, Nigel J.
AU - Cao, Chuanhai
AU - Carlson, Chris S.
AU - Carlsson, Cynthia M.
AU - Carney, Regina M.
AU - Carrasquillo, Minerva M.
AU - Carroll, Steven L.
AU - Diaz, Carolina Ceballos
AU - Chui, Helena C.
AU - Clark, David G.
AU - Cribbs, David H.
AU - Crocco, Elizabeth A.
AU - Decarli, Charles
AU - Dick, Malcolm
AU - Duara, Ranjan
AU - Evans, Denis A.
AU - Faber, Kelley M.
AU - Fallon, Kenneth B.
AU - Fardo, David W.
AU - Farlow, Martin R.
AU - Ferris, Steven
AU - Foroud, Tatiana M.
AU - Galasko, Douglas R.
AU - Gearing, Marla
AU - Geschwind, Daniel H.
AU - Gilbert, John R.
AU - Graff-Radford, Neill R.
AU - Green, Robert C.
AU - Growdon, John H.
AU - Hamilton, Ronald L.
AU - Harrell, Lindy E.
AU - Honig, Lawrence S.
AU - Huentelman, Matthew J.
AU - Hulette, Christine M.
AU - Hyman, Bradley T.
AU - Jarvik, Gail P.
AU - Abner, Erin
AU - Jin, Lee Way
AU - Jun, Gyungah
AU - Karydas, Anna
AU - Kaye, Jeffrey A.
AU - Kim, Ronald
AU - Kowall, Neil W.
AU - Kramer, Joel H.
AU - Laferla, Frank M.
AU - Lah, James J.
AU - Leverenz, James B.
AU - Levey, Allan I.
AU - Li, Ge
AU - Lieberman, Andrew P.
AU - Lunetta, Kathryn L.
AU - Lyketsos, Constantine G.
AU - Marson, Daniel C.
AU - Martiniuk, Frank
AU - Mash, Deborah C.
AU - Masliah, Eliezer
AU - McCormick, Wayne C.
AU - McCurry, Susan M.
AU - McDavid, Andrew N.
AU - McKee, Ann C.
AU - Mesulam, Marsel
AU - Miller, Bruce L.
AU - Miller, Carol A.
AU - Miller, Joshua W.
AU - Murrell, Jill R.
AU - Myers, Amanda J.
AU - O'Bryant, Sid
AU - Olichney, John M.
AU - Pankratz, Vernon S.
AU - Parisi, Joseph E.
AU - Paulson, Henry L.
AU - Perry, William
AU - Peskind, Elaine
AU - Pierce, Aimee
AU - Poon, Wayne W.
AU - Potter, Huntington
AU - Quinn, Joseph F.
AU - Raj, Ashok
AU - Raskind, Murray
AU - Reisberg, Barry
AU - Reitz, Christiane
AU - Ringman, John M.
AU - Roberson, Erik D.
AU - Rogaeva, Ekaterina
AU - Rosen, Howard J.
AU - Rosenberg, Roger N.
AU - Sager, Mark A.
AU - Saykin, Andrew J.
AU - Schneider, Julie A.
AU - Schneider, Lon S.
AU - Seeley, William W.
AU - Smith, Amanda G.
AU - Sonnen, Joshua A.
AU - Spina, Salvatore
AU - Stern, Robert A.
AU - Swerdlow, Russell H.
AU - Tanzi, Rudolph E.
AU - Thornton-Wells, Tricia A.
AU - Trojanowski, John Q.
AU - Troncoso, Juan C.
AU - Van Deerlin, Vivianna M.
AU - Van Eldik, Linda J.
AU - Vinters, Harry V.
AU - Vonsattel, Jean Paul
AU - Weintraub, Sandra
AU - Welsh-Bohmer, Kathleen A.
AU - Wilhelmsen, Kirk C.
AU - Williamson, Jennifer
AU - Wingo, Thomas S.
AU - Woltjer, Randall L.
AU - Wright, Clinton B.
AU - Yu, Chang En
AU - Yu, Lei
AU - Garzia, Fabienne
AU - Golamaully, Feroze
AU - Septier, Gislain
AU - Engelborghs, Sebastien
AU - Vandenberghe, Rik
AU - De Deyn, Peter P.
AU - Fernadez, Carmen Muñoz
AU - Benito, Yoland Aladro
AU - Thonberg, Hakan
AU - Forsell, Charlotte
AU - Lilius, Lena
AU - Kinhult-Stählbom, Anne
AU - Kilander, Lena
AU - Brundin, Rosemarie
AU - Concari, Letizia
AU - Helisalmi, Seppo
AU - Koivisto, Anne Maria
AU - Haapasalo, Annakaisa
AU - Dermecourt, Vincent
AU - Fievet, Nathalie
AU - Hanon, Olivier
AU - Dufouil, Carole
AU - Brice, Alexis
AU - Ritchie, Karen
AU - Dubois, Bruno
AU - Himali, Jayanadra J.
AU - Keene, C. Dirk
AU - Tschanz, Joann
AU - Fitzpatrick, Annette L.
AU - Kukull, Walter A.
AU - Norton, Maria
AU - Aspelund, Thor
AU - Larson, Eric B.
AU - Munger, Ron
AU - Rotter, Jerome I.
AU - Lipton, Richard B.
AU - Bullido, María J.
AU - Hofman, Albert
AU - Montine, Thomas J.
AU - Coto, Eliecer
AU - Boerwinkle, Eric
AU - Petersen, Ronald C.
AU - Alvarez, Victoria
AU - Rivadeneira, Fernando
AU - Reiman, Eric M.
AU - Gallo, Maura
AU - O'Donnell, Christopher J.
AU - Reisch, Joan S.
AU - Bruni, Amalia Cecilia
AU - Royall, Donald R.
AU - Dichgans, Martin
AU - Sano, Mary
AU - Galimberti, Daniela
AU - St George-Hyslop, Peter
AU - Scarpini, Elio
AU - Tsuang, Debby W.
AU - Mancuso, Michelangelo
AU - Bonuccelli, Ubaldo
AU - Winslow, Ashley R.
AU - Daniele, Antonio
AU - Wu, Chuang Kuo
AU - Peters, Oliver
AU - Nacmias, Benedetta
AU - Riemenschneider, Matthias
AU - Heun, Reinhard
AU - Brayne, Carol
AU - Rubinsztein, David C.
AU - Bras, Jose
AU - Guerreiro, Rita
AU - Al-Chalabi, Ammar
AU - Shaw, Christopher E.
AU - Collinge, John
AU - Mann, David
AU - Clarimón, Jordi
AU - Sussams, Rebecca
AU - Lovestone, Simon
AU - O'Donovan, Michael C.
AU - Owen, Michael J.
AU - Behrens, Timothy W.
AU - Mead, Simon
AU - Uitterlinden, Andre G.
AU - Holmes, Clive
AU - Cruchaga, Carlos
AU - Ingelsson, Martin
AU - Bennett, David A.
AU - Powell, John
AU - Golde, Todd E.
AU - Graff, Caroline
AU - De Jager, Philip L.
AU - Morgan, Kevin
AU - Ertekin-Taner, Nilufer
AU - Combarros, Onofre
AU - Psaty, Bruce M.
AU - Passmore, Peter
AU - Younkin, Steven G.
AU - Berr, Claudine
AU - Gudnason, Vilmundur
AU - Rujescu, Dan
AU - Dickson, Dennis W.
AU - Dartigues, Jean François
AU - Destefano, Anita L.
AU - Ortega-Cubero, Sara
AU - Hakonarson, Hakon
AU - Campion, Dominique
AU - Boada, Merce
AU - Kauwe, John Keoni
AU - Farrer, Lindsay A.
AU - Van Broeckhoven, Christine
AU - Ikram, M. Arfan
AU - Jones, Lesley
AU - Haines, Jonathan L.
AU - Tzourio, Christophe
AU - Launer, Lenore J.
AU - Escott-Price, Valentina
AU - Mayeux, Richard
AU - Deleuze, Jean François
AU - Amin, Najaf
AU - Goate, Alison M.
AU - Pericak-Vance, Margaret A.
AU - Holmans, Peter A.
AU - Van Duijn, Cornelia M.
AU - Ramirez, Alfredo
AU - Wang, Li San
AU - Lambert, Jean Charles
AU - Seshadri, Sudha
AU - Williams, Julie
AU - Schellenberg, Gerard D.
N1 - Funding Information: as part of collaboration between INSERM, Victor Segalen Bordeaux II University, and Sanofi-Synthelabo. 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 Salaries, 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, Agence Nationale de la Recherche (ANR supported the COGINUT and COVADIS projects), Fondation de France, and the joint French Ministry of Research/INSERM ‘Cohortes et Collections de Données Biologiques’ program. The Lille Genopole received an unconditional grant from Eisai and was supported by the European Joint Programme for Neurodegenerative Disease (JPND: grant MR/L501517/1). The Three-City Biological Bank was developed and maintained by the Laboratory for Genomic Analysis LAG-BRC, Institut Pasteur de Lille. Funding Information: GERAD/PERADES. We thank all individuals who participated in this study. Cardiff University was supported by the Alzheimer’s Society (AS; grant RF014/164) and the Medical Research Council (MRC; grants G0801418/1, MR/K013041/1, MR/L023784/1) (R. Sims is an AS Research Fellow). Cardiff University was also supported by the European Joint Programme for Neurodegenerative Disease (JPND; grant MR/L501517/1), Alzheimer’s Research UK (ARUK; grant ARUK-PG2014-1), the Welsh Assembly Government (grant SGR544:CADR), and a donation from the Moondance Charitable Foundation. Cardiff University acknowledges the support of the UK Dementia Research Institute, of which J. Williams is an associate director. Cambridge University acknowledges support from the MRC. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and NIHR Queen Square Dementia Biomedical Research Unit. The University of Southampton acknowledges support from the AS. King’s College London was supported by the NIHR Biomedical Research Centre for Mental Health and the Biomedical Research Unit for Dementia at the South London and Maudsley NHS Foundation Trust and by King’s College London and the MRC. ARUK and the Big Lottery Fund provided support to Nottingham University. Ulster Garden Villages, AS, ARUK, the American Federation for Aging Research, and the Northern Ireland R&D Office provided support for Queen’s University, Belfast. The Centro de Biología Molecular Severo Ochoa (CSIS-UAM), CIBERNED, Instituto de Investigación Sanitaria la Paz, University Hospital La Paz, and the Universidad Autónoma de Madrid were supported by grants from the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III) and by an institutional grant of the Fundación Ramón Areces to the CMBSO. We thank I. Sastre and A. Martinez-Garcia for DNA preparation, and P. Gil and P. Coria for their recruitment efforts. The Department of Neurology, University Hospital Mútua de Terrassa, was supported by CIBERNED, Instituto de Salud Carlos III, Madrid, Spain, and acknowledges M.A. Pastor (University of Navarra Medical School and Center for Applied Medical Research), M. Seijo-Martinez (Hospital do Salnes), and R. Rene, J. Gascon, and J. Campdelacreu (Hospital de Bellvitage) for providing DNA samples. The Hospital de la Sant Pau, Universitat Autònoma de Barcelona, acknowledges support from the Spanish Ministry of Economy and Competitiveness (grant PI12/01311) and from the Generalitat de Catalunya (2014SGR-235). The Santa Lucia Foundation and the Fondazione Ca’ Granda IRCCS Ospedale Policlinico, Italy, acknowledge the Italian Ministry of Health (grant RC 10.11.12.13/A). The Bonn samples are part of the German Dementia Competence Network (DCN) and the German Research Network on Degenerative Dementia (KNDD), which are funded by the German Federal Ministry of Education and Research (grants KND: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434; grants KNDD: 01GI1007A, 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). M.M.N. is a member of the German Research Foundation (DFG) cluster of excellence ImmunoSensation. Funding for Saarland University was provided by the German Federal Ministry of Education and Research (BMBF), grant 01GS08125, to M. Riemenschneider. The University of Washington was supported by grants from the US National Institutes of Health (R01-NS085419 and R01-AG044546), the Alzheimer’s Association (NIRG-11-200110), and the American Federation for Aging Research (C. Cruchaga was recipient of a New Investigator Award in Alzheimer’s disease). Brigham Young University was supported by the Alzheimer’s Association (MNIRG-11-205368), the BYU Gerontology Program, and the US National Institutes of Health (R01-AG11380, R01-AG021136, P30-S069329-01, R01-AG042611). We also acknowledge funding from the Institute of Neurology, UCL, London, who was supported in part by ARUK via an anonymous donor, and by a fellowship to R.G. The participation of D.S., M.U., and C. Masullo in the study was completely supported by Ministero della Salute, IRCCS Research Program, Ricerca Corrente 2015–2017, Linea 2 ‘Malattiecomplesse e Terapie Innovative’ and by the ‘5 × 1000’ voluntary contribution. AddNeuromed is supported by InnoMed, an Integrated Project funded by the European Union’s Sixth Framework Programme priority FP6-2004-LIFESCIHEALTH-5, Life Sciences, Genomics, and Biotechnology for Health. We are grateful to the Wellcome Trust for awarding a Principal Research Fellowship to D.C.R. (095317/Z/11/Z). M. Riemenschneider was funded by BMBF NGFN grant 01GS08125. B.N. was supported by the Fondazione Cassa di Risparmio di Pistoia e Pescia (grants 2014.0365, 2011.0264, 2013.0347). H. Hampel is supported by the AXA Research Fund, the Fondation Universite Pierre et Marie Curie, and the ‘Fondation pour la Recherche sur Alzheimer’, Paris, France. The research leading to these results has received funding from the program ‘Investissements d’Avenir’, ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6. CHARGE. Infrastructure for the CHARGE Consortium is supported in part by National Heart, Lung, and Blood Institute grant HL105756 and for the neurology working group by AG033193 and AG049505. Rotterdam (RS). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. Generation and management of the Illumina exome chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine (http://www.glimdna. org/), Erasmus MC, Rotterdam, the Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project 050-060-810); the Netherlands Organization for Scientific Research (NWO; project 184021007); and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; http://www.bbmri.nl). Generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Funding Information: The Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation. Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901, and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research. Funding Information: Belgium sample collection. Research at the Antwerp site is funded in part by the Interuniversity Attraction Poles program of the Belgian Science Policy Office, the Foundation for Alzheimer Research (SAO-FRA), a Methusalem Excellence Grant of the Flemish Government, the Research Foundation Flanders (FWO), and the Special Research Fund of the University of Antwerp, Belgium. Authors from the Antwerp site thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge, and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and University Hospitals Leuven. Funding Information: Finnish sample collection. Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Center of Excellence in Neurodegeneration. Swedish sample collection. Sample collection was financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), King Gustaf V and Queen Victoria’s Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between the Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation, and the Swedish Alzheimer Foundation. AMP AD University of Florida/Mayo Clinic/Institutes of Systems Biology. For human brain donations, we thank all patients and their families, without whom this work would not have been possible. This work was supported by NIH/NIA AG046139-01 (T.E.G., N.E.-T., N.P., S.G.Y.). We thank T.G. Beach (Banner Sun Health Institute) for sharing human tissue. Publisher Copyright: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 '4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 '8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
AB - We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 '4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 '8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
UR - http://www.scopus.com/inward/record.url?scp=85028725970&partnerID=8YFLogxK
U2 - 10.1038/ng.3916
DO - 10.1038/ng.3916
M3 - Article
C2 - 28714976
AN - SCOPUS:85028725970
SN - 1061-4036
VL - 49
SP - 1373
EP - 1384
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -