Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Brian W. Kunkle, Benjamin Grenier-Boley, Rebecca Sims, Joshua C. Bis, Vincent Damotte, Adam C. Naj, Anne Boland, Maria Vronskaya, Sven J. van der Lee, Alexandre Amlie-Wolf, Céline Bellenguez, Aura Frizatti, Vincent Chouraki, Eden R. Martin, Kristel Sleegers, Nandini Badarinarayan, Johanna Jakobsdottir, Kara L. Hamilton-Nelson, Sonia Moreno-Grau, Robert OlasoRachel Raybould, Yuning Chen, Amanda B. Kuzma, Mikko Hiltunen, Taniesha Morgan, Shahzad Ahmad, Badri N. Vardarajan, Jacques Epelbaum, Per Hoffmann, Merce Boada, Gary W. Beecham, Jean Guillaume Garnier, Denise Harold, Annette L. Fitzpatrick, Otto Valladares, Marie Laure Moutet, Amy Gerrish, Albert V. Smith, Liming Qu, Delphine Bacq, Nicola Denning, Xueqiu Jian, Yi Zhao, Maria Del Zompo, Nick C. Fox, Seung Hoan Choi, Ignacio Mateo, Joseph T. Hughes, Hieab H. Adams, John Malamon, Florentino Sanchez-Garcia, Yogen Patel, Jennifer A. Brody, Beth A. Dombroski, Maria Candida Deniz Naranjo, Makrina Daniilidou, Gudny Eiriksdottir, Shubhabrata Mukherjee, David Wallon, James Uphill, Thor Aspelund, Laura B. Cantwell, Fabienne Garzia, Daniela Galimberti, Edith Hofer, Mariusz Butkiewicz, Bertrand Fin, Elio Scarpini, Chloe Sarnowski, Will S. Bush, Stéphane Meslage, Johannes Kornhuber, Charles C. White, Yuenjoo Song, Robert C. Barber, Sebastiaan Engelborghs, Sabrina Sordon, Dina Voijnovic, Perrie M. Adams, Rik Vandenberghe, Manuel Mayhaus, L. Adrienne Cupples, Marilyn S. Albert, Peter P. De Deyn, Wei Gu, Jayanadra J. Himali, Duane Beekly, Alessio Squassina, Annette M. Hartmann, Adelina Orellana, Deborah Blacker, Eloy Rodriguez-Rodriguez, Simon Lovestone, Melissa E. Garcia, Rachelle S. Doody, Carmen Munoz-Fernadez, Rebecca Sussams, Honghuang Lin, Thomas J. Fairchild, Yolanda A. Benito, Clive Holmes, Hata Karamujić-Čomić, Matthew P. Frosch, Hakan Thonberg, Wolfgang Maier, Gena Roschupkin, Bernardino Ghetti, Vilmantas Giedraitis, Amit Kawalia, Shuo Li, Ryan M. Huebinger, Lena Kilander, Susanne Moebus, Isabel Hernández, M. Ilyas Kamboh, Rose Marie Brundin, James Turton, Qiong Yang, Mindy J. Katz, Letizia Concari, Jenny Lord, Alexa S. Beiser, C. Dirk Keene, Seppo Helisalmi, Iwona Kloszewska, Walter A. Kukull, Anne Maria Koivisto, Aoibhinn Lynch, Lluís Tarraga, Eric B. Larson, Annakaisa Haapasalo, Brian Lawlor, Thomas H. Mosley, Richard B. Lipton, Vincenzo Solfrizzi, Michael Gill, W. T. Longstreth, Thomas J. Montine, Vincenza Frisardi, Monica Diez-Fairen, Fernando Rivadeneira, Ronald C. Petersen, Vincent Deramecourt, Ignacio Alvarez, Francesca Salani, Antonio Ciaramella, Eric Boerwinkle, Eric M. Reiman, Nathalie Fievet, Jerome I. Rotter, Joan S. Reisch, Olivier Hanon, Chiara Cupidi, A. G. Andre Uitterlinden, Donald R. Royall, Carole Dufouil, Raffaele Giovanni Maletta, Itziar de Rojas, Mary Sano, Alexis Brice, Roberta Cecchetti, Peter St George-Hyslop, Karen Ritchie, Magda Tsolaki, Debby W. Tsuang, Bruno Dubois, David Craig, Chuang Kuo Wu, Hilkka Soininen, Despoina Avramidou, Roger L. Albin, Laura Fratiglioni, Antonia Germanou, Liana G. Apostolova, Lina Keller, Maria Koutroumani, Steven E. Arnold, Francesco Panza, Olymbia Gkatzima, Sanjay Asthana, Didier Hannequin, Patrice Whitehead, Craig S. Atwood, Paolo Caffarra, Harald Hampel, Inés Quintela, Ángel Carracedo, Lars Lannfelt, David C. Rubinsztein, Lisa L. Barnes, Florence Pasquier, Lutz Frölich, Sandra Barral, Bernadette McGuinness, Thomas G. Beach, Janet A. Johnston, James T. Becker, Peter Passmore, Eileen H. Bigio, Jonathan M. Schott, Thomas D. Bird, Jason D. Warren, Bradley F. Boeve, Michelle K. Lupton, James D. Bowen, Petra Proitsi, Adam Boxer, John F. Powell, James R. Burke, John S.K. Kauwe, Jeffrey M. Burns, Michelangelo Mancuso, Joseph D. Buxbaum, Ubaldo Bonuccelli, Nigel J. Cairns, Andrew McQuillin, Chuanhai Cao, Gill Livingston, Chris S. Carlson, Nicholas J. Bass, Cynthia M. Carlsson, John Hardy, Regina M. Carney, Jose Bras, Minerva M. Carrasquillo, Rita Guerreiro, Mariet Allen, Helena C. Chui, Elizabeth Fisher, Carlo Masullo, Elizabeth A. Crocco, Charles DeCarli, Gina Bisceglio, Malcolm Dick, Li Ma, Ranjan Duara, Neill R. Graff-Radford, Denis A. Evans, Angela Hodges, Kelley M. Faber, Martin Scherer, Kenneth B. Fallon, Matthias Riemenschneider, David W. Fardo, Reinhard Heun, Martin R. Farlow, Heike Kölsch, Steven Ferris, Markus Leber, Tatiana M. Foroud, Isabella Heuser, Douglas R. Galasko, Ina Giegling, Marla Gearing, Michael Hüll, Daniel H. Geschwind, John R. Gilbert, John C. Morris, Robert C. Green, Kevin Mayo, John H. Growdon, Thomas Feulner, Ronald L. Hamilton, Lindy E. Harrell, Dmitriy Drichel, Lawrence S. Honig, Thomas D. Cushion, Matthew J. Huentelman, Paul Hollingworth, Christine M. Hulette, Bradley T. Hyman, Rachel Marshall, Gail P. Jarvik, Alun Meggy, Erin Abner, Georgina E. Menzies, Lee Way Jin, Ganna Leonenko, Luis M. Real, Gyungah R. Jun, Clinton T. Baldwin, Detelina Grozeva, Anna Karydas, Giancarlo Russo, Jeffrey A. Kaye, Ronald Kim, Frank Jessen, Neil W. Kowall, Bruno Vellas, Joel H. Kramer, Emma Vardy, Frank M. LaFerla, Karl Heinz Jöckel, James J. Lah, Martin Dichgans, James B. Leverenz, David Mann, Allan I. Levey, Stuart Pickering-Brown, Andrew P. Lieberman, Norman Klopp, Kathryn L. Lunetta, H. Erich Wichmann, Constantine G. Lyketsos, Kevin Morgan, Daniel C. Marson, Kristelle Brown, Frank Martiniuk, Christopher Medway, Deborah C. Mash, Markus M. Nöthen, Eliezer Masliah, Nigel M. Hooper, Wayne C. McCormick, Antonio Daniele, Susan M. McCurry, Anthony Bayer, Andrew N. McDavid, John Gallacher, Ann C. McKee, Hendrik van den Bussche, Marsel Mesulam, Carol Brayne, Bruce L. Miller, Steffi Riedel-Heller, Carol A. Miller, Joshua W. Miller, Ammar Al-Chalabi, John C. Morris, Christopher E. Shaw, Amanda J. Myers, Jens Wiltfang, Sid O’Bryant, John M. Olichney, Victoria Alvarez, Joseph E. Parisi, Andrew B. Singleton, Henry L. Paulson, John Collinge, William R. Perry, Simon Mead, Elaine Peskind, David H. Cribbs, Martin Rossor, Aimee Pierce, Natalie S. Ryan, Wayne W. Poon, Benedetta Nacmias, Huntington Potter, Sandro Sorbi, Joseph G. Quinn, Eleonora Sacchinelli, Ashok Raj, Gianfranco Spalletta, Murray Raskind, Carlo Caltagirone, Paola Bossù, Maria Donata Orfei, Barry Reisberg, Robert Clarke, Christiane Reitz, A. David Smith, John M. Ringman, Donald Warden, Erik D. Roberson, Gordon Wilcock, Ekaterina Rogaeva, Amalia Cecilia Bruni, Howard J. Rosen, Maura Gallo, Roger N. Rosenberg, Yoav Ben-Shlomo, Mark A. Sager, Patrizia Mecocci, Andrew J. Saykin, Pau Pastor, Michael L. Cuccaro, Jeffery M. Vance, Julie A. Schneider, Lori S. Schneider, Susan Slifer, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Russell H. Swerdlow, Mitchell Tang, Rudolph E. Tanzi, 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, Yasaman Saba, Alberto Pilotto, Maria J. Bullido, Oliver Peters, Paul K. Crane, David Bennett, Paola Bosco, Eliecer Coto, Virginia Boccardi, Phil L. De Jager, Alberto Lleo, Nick Warner, Oscar L. Lopez, Martin Ingelsson, Panagiotis Deloukas, Carlos Cruchaga, Caroline Graff, Rhian Gwilliam, Myriam Fornage, Alison M. Goate, Pascual Sanchez-Juan, Patrick G. Kehoe, Najaf Amin, Nilifur Ertekin-Taner, Claudine Berr, Stéphanie Debette, Seth Love, Lenore J. Launer, Steven G. Younkin, Jean Francois Dartigues, Chris Corcoran, M. Arfan Ikram, Dennis W. Dickson, Gael Nicolas, Dominique Campion, Jo Ann Tschanz, Helena Schmidt, Hakon Hakonarson, Jordi Clarimon, Ron Munger, Reinhold Schmidt, Lindsay A. Farrer, Christine Van Broeckhoven, Michael C. O’Donovan, Anita L. DeStefano, Lesley Jones, Jonathan L. Haines, Jean Francois Deleuze, Michael J. Owen, Vilmundur Gudnason, Richard Mayeux, Valentina Escott-Price, Bruce M. Psaty, Alfredo Ramirez, Li San Wang, Agustin Ruiz, Cornelia M. van Duijn, Peter A. Holmans, Sudha Seshadri, Julie Williams, Phillippe Amouyel, Gerard D. Schellenberg, Jean Charles Lambert, Margaret A. Pericak-Vance

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Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Original languageEnglish
Pages (from-to)414-430
Number of pages17
JournalNature Genetics
Volume51
Issue number3
Early online date28 Feb 2019
DOIs
Publication statusPublished - 28 Feb 2019

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    Kunkle, B. W., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., Boland, A., Vronskaya, M., van der Lee, S. J., Amlie-Wolf, A., Bellenguez, C., Frizatti, A., Chouraki, V., Martin, E. R., Sleegers, K., Badarinarayan, N., Jakobsdottir, J., Hamilton-Nelson, K. L., Moreno-Grau, S., ... Pericak-Vance, M. A. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(3), 414-430. https://doi.org/10.1038/s41588-019-0358-2