Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Rebecca Sims, Sven J. Van Der Lee, Adam C. Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W. Kunkle, Anne Boland, Rachel Raybould, Joshua C. Bis, Eden R. Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B. Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R. Graham, Robert OlasoPer Hoffmann, Megan L. Grove, Badri N. Vardarajan, Mikko Hiltunen, Markus M. Nöthen, Charles C. White, Kara L. Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung Hoan Choi, Gary W. Beecham, Cécile Dulary, Stefan Herms, Albert V. Smith, Cory C. Funk, Céline Derbois, Andreas J. Forstner, Shahzad Ahmad, Hongdong Li, Delphine Bacq, Denise Harold, Claudia L. Satizabal, Otto Valladares, Alessio Squassina, Rhodri Thomas, Jennifer A. Brody, Liming Qu, Pascual Sánchez-Juan, Taniesha Morgan, Frank J. Wolters, Yi Zhao, Florentino Sanchez Garcia, Nicola Denning, Myriam Fornage, John Malamon, Maria Candida Deniz Naranjo, Elisa Majounie, Thomas H. Mosley, Beth Dombroski, David Wallon, Michelle K. Lupton, Josée Dupuis, Patrice Whitehead, Laura Fratiglioni, Christopher Medway, Xueqiu Jian, Shubhabrata Mukherjee, Lina Keller, Kristelle Brown, Honghuang Lin, Laura B. Cantwell, Francesco Panza, Bernadette McGuinness, Sonia Moreno-Grau, Jeremy D. Burgess, Vincenzo Solfrizzi, Petra Proitsi, Hieab H. Adams, Mariet Allen, Davide Seripa, Pau Pastor, L. Adrienne Cupples, Nathan D. Price, Didier Hannequin, Ana Frank-García, Daniel Levy, Paramita Chakrabarty, Paolo Caffarra, Ina Giegling, Alexa S. Beiser, Vilmantas Giedraitis, Harald Hampel, Melissa E. Garcia, Xue Wang, Lars Lannfelt, Patrizia Mecocci, Gudny Eiriksdottir, Paul K. Crane, Florence Pasquier, Virginia Boccardi, Isabel Henández, Robert C. Barber, Martin Scherer, Lluis Tarraga, Perrie M. Adams, Markus Leber, Yuning Chen, Marilyn S. Albert, Steffi Riedel-Heller, Valur Emilsson, Duane Beekly, Anne Braae, Reinhold Schmidt, Deborah Blacker, Carlo Masullo, Helena Schmidt, Rachelle S. Doody, Gianfranco Spalletta, W. T. Longstreth, Thomas J. Fairchild, Paola Bossù, Oscar L. Lopez, Matthew P. Frosch, Eleonora Sacchinelli, Bernardino Ghetti, Qiong Yang, Ryan M. Huebinger, Frank Jessen, Shuo Li, M. Ilyas Kamboh, John C. Morris, Oscar Sotolongo-Grau, Mindy J. Katz, Chris Corcoran, Melanie Dunstan, Amy Braddel, Charlene Thomas, Alun Meggy, Rachel Marshall, Amy Gerrish, Jade Chapman, Miquel Aguilar, Sarah Taylor, Matt Hill, Mònica Díez Fairén, Angela Hodges, Bruno Vellas, Hilkka Soininen, Iwona Kloszewska, Makrina Daniilidou, James Uphill, Yogen Patel, Joseph T. Hughes, Jenny Lord, James Turton, Annette M. Hartmann, Roberta Cecchetti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Carlo Caltagirone, Maria Donata Orfei, Antonio Ciaramella, Sabrina Pichler, Manuel Mayhaus, Wei Gu, Alberto Lleó, Juan Fortea, Rafael Blesa, Imelda S. Barber, Keeley Brookes, Chiara Cupidi, Raffaele Giovanni Maletta, David Carrell, Sandro Sorbi, Susanne Moebus, Maria Urbano, Alberto Pilotto, Johannes Kornhuber, Paolo Bosco, Stephen Todd, David Craig, Janet Johnston, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Nick C. Fox, John Hardy, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig S. Atwood, Clinton T. Baldwin, Lisa L. Barnes, Sandra Barral, Thomas G. Beach, James T. Becker, Eileen H. Bigio, Thomas D. Bird, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Jeffrey M. Burns, Joseph D. Buxbaum, Nigel J. Cairns, Chuanhai Cao, Chris S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Carolina Ceballos Diaz, Helena C. Chui, David G. Clark, David H. Cribbs, Elizabeth A. Crocco, Charles Decarli, Malcolm Dick, Ranjan Duara, Denis A. Evans, Kelley M. Faber, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow, Steven Ferris, Tatiana M. Foroud, Douglas R. Galasko, Marla Gearing, Daniel H. Geschwind, John R. Gilbert, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Ronald L. Hamilton, Lindy E. Harrell, Lawrence S. Honig, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Erin Abner, Lee Way Jin, Gyungah Jun, Anna Karydas, Jeffrey A. Kaye, Ronald Kim, Neil W. Kowall, Joel H. Kramer, Frank M. Laferla, James J. Lah, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Kathryn L. Lunetta, Constantine G. Lyketsos, Daniel C. Marson, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Jill R. Murrell, Amanda J. Myers, Sid O'Bryant, John M. Olichney, Vernon S. Pankratz, Joseph E. Parisi, Henry L. Paulson, William Perry, Elaine Peskind, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Mark A. Sager, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Russell H. Swerdlow, Rudolph E. Tanzi, Tricia A. Thornton-Wells, John Q. Trojanowski, Juan C. Troncoso, Vivianna M. Van Deerlin, Linda J. Van Eldik, Harry V. Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Kirk C. Wilhelmsen, Jennifer Williamson, Thomas S. Wingo, Randall L. Woltjer, Clinton B. Wright, Chang En Yu, Lei Yu, Fabienne Garzia, Feroze Golamaully, Gislain Septier, Sebastien Engelborghs, Rik Vandenberghe, Peter P. De Deyn, Carmen Muñoz Fernadez, Yoland Aladro Benito, Hakan Thonberg, Charlotte Forsell, Lena Lilius, Anne Kinhult-Stählbom, Lena Kilander, Rosemarie Brundin, Letizia Concari, Seppo Helisalmi, Anne Maria Koivisto, Annakaisa Haapasalo, Vincent Dermecourt, Nathalie Fievet, Olivier Hanon, Carole Dufouil, Alexis Brice, Karen Ritchie, Bruno Dubois, Jayanadra J. Himali, C. Dirk Keene, Joann Tschanz, Annette L. Fitzpatrick, Walter A. Kukull, Maria Norton, Thor Aspelund, Eric B. Larson, Ron Munger, Jerome I. Rotter, Richard B. Lipton, María J. Bullido, Albert Hofman, Thomas J. Montine, Eliecer Coto, Eric Boerwinkle, Ronald C. Petersen, Victoria Alvarez, Fernando Rivadeneira, Eric M. Reiman, Maura Gallo, Christopher J. O'Donnell, Joan S. Reisch, Amalia Cecilia Bruni, Donald R. Royall, Martin Dichgans, Mary Sano, Daniela Galimberti, Peter St George-Hyslop, Elio Scarpini, Debby W. Tsuang, Michelangelo Mancuso, Ubaldo Bonuccelli, Ashley R. Winslow, Antonio Daniele, Chuang Kuo Wu, Oliver Peters, Benedetta Nacmias, Matthias Riemenschneider, Reinhard Heun, Carol Brayne, David C. Rubinsztein, Jose Bras, Rita Guerreiro, Ammar Al-Chalabi, Christopher E. Shaw, John Collinge, David Mann, Jordi Clarimón, Rebecca Sussams, Simon Lovestone, Michael C. O'Donovan, Michael J. Owen, Timothy W. Behrens, Simon Mead, Andre G. Uitterlinden, Andre G. Uitterlinden, Carlos Cruchaga, Martin Ingelsson, David A. Bennett, John Powell, Todd E. Golde, Caroline Graff, Philip L. De Jager, Kevin Morgan, Nilufer Ertekin-Taner, Onofre Combarros, Bruce M. Psaty, Peter Passmore, Steven G. Younkin, Claudine Berr, Vilmundur Gudnason, Dan Rujescu, Dennis W. Dickson, Jean François Dartigues, Anita L. Destefano, Sara Ortega-Cubero, Hakon Hakonarson, Dominique Campion, Merce Boada, John Keoni Kauwe, Lindsay A. Farrer, Christine Van Broeckhoven, M. Arfan Ikram, Lesley Jones, Jonathan L. Haines, Christophe Tzourio, Lenore J. Launer, Valentina Escott-Price, Richard Mayeux, Jean François Deleuze, Najaf Amin, Alison M. Goate, Margaret A. Pericak-Vance, Peter A. Holmans, Cornelia M. Van Duijn, Alfredo Ramirez, Li San Wang, Jean Charles Lambert, Sudha Seshadri, Julie Williams, Gerard D. Schellenberg

Research output: Contribution to journalArticle

228 Scopus citations

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 languageEnglish (US)
Pages (from-to)1373-1384
Number of pages12
JournalNature genetics
Volume49
Issue number9
DOIs
StatePublished - Sep 1 2017

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ASJC Scopus subject areas

  • Genetics

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Sims, R., Van Der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B. W., Boland, A., Raybould, R., Bis, J. C., Martin, E. R., Grenier-Boley, B., Heilmann-Heimbach, S., Chouraki, V., Kuzma, A. B., Sleegers, K., Vronskaya, M., Ruiz, A., Graham, R. R., ... Schellenberg, G. D. (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature genetics, 49(9), 1373-1384. https://doi.org/10.1038/ng.3916