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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-03

AUTHORS

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 Olaso, Rachel 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, RoseMarie 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 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 F. 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, JoAnn 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

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. More... »

PAGES

414-430

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    3

    VOLUME

    51

    Author Affiliations

  • University of Miami
  • Pasteur Institute of Lille
  • Cardiff University
  • University of Washington
  • University of Pennsylvania
  • Erasmus University Medical Center
  • Boston University School of Medicine
  • University of Antwerp
  • Icelandic Heart Association
  • Instituto de Salud Carlos III
  • Boston University
  • Kuopio University Hospital
  • Columbia University
  • University of Basel
  • Dublin City University
  • University College London
  • University of Iceland
  • The University of Texas Health Science Center at Houston
  • University of Cagliari
  • International University Of Catalonia
  • King's College London
  • Aristotle University of Thessaloniki
  • Centre Hospitalier Universitaire De Rouen
  • Medical Research Council
  • University of Milan
  • Medical University of Graz
  • Case Western Reserve University
  • University of Erlangen-Nuremberg
  • Broad Institute
  • University of North Texas Health Science Center
  • The University of Texas Southwestern Medical Center
  • KU Leuven
  • Johns Hopkins University
  • Martin Luther University Halle-Wittenberg
  • Harvard University
  • University of Oxford
  • National Institute on Aging
  • Baylor College of Medicine
  • University of Southampton
  • Massachusetts General Hospital
  • Karolinska Institute
  • University of Bonn
  • Indiana University – Purdue University Indianapolis
  • Uppsala University
  • University of Pittsburgh
  • Albert Einstein College of Medicine
  • University of Parma
  • Medical University of Lodz
  • St. James's Hospital
  • Kaiser Permanente Washington Health Research Institute
  • University of Eastern Finland
  • University of Mississippi Medical Center
  • University of Bari Aldo Moro
  • University Hospital Mútua de Terrassa
  • Mayo Clinic
  • Centre Hospitalier Regional et Universitaire de Lille
  • Fondazione Santa Lucia
  • University of Arizona
  • Harbor–UCLA Medical Center
  • Paris Descartes University
  • The University of Texas Health Science Center at San Antonio
  • Centre Hospitalier Universitaire de Bordeaux
  • Icahn School of Medicine at Mount Sinai
  • Pitié-Salpêtrière Hospital
  • University of Perugia
  • University of Toronto
  • University of Edinburgh
  • French National Centre for Scientific Research
  • Queen's University Belfast
  • Texas Tech University Health Sciences Center
  • VA Ann Arbor Healthcare System
  • Stockholm University
  • University of Wisconsin–Madison
  • University of Santiago de Compostela
  • University of Cambridge
  • Rush University Medical Center
  • Heidelberg University
  • Banner Sun Health Research Institute
  • Northwestern University
  • QIMR Berghofer Medical Research Institute
  • Swedish Medical Center
  • University of California, San Francisco
  • Duke University
  • Brigham Young University
  • University of Kansas Medical Center
  • University of Pisa
  • Washington University in St. Louis
  • University of South Florida
  • Fred Hutchinson Cancer Research Center
  • Bruce W. Carter VA Medical Center
  • Mayo Clinic
  • University of Southern California
  • Catholic University of the Sacred Heart
  • University of California, Davis
  • University of California, Irvine
  • Mount Sinai Medical Center
  • University Medical Center Hamburg-Eppendorf
  • University of Alabama at Birmingham
  • University of Kentucky
  • New York University
  • University of Cologne
  • Charité
  • University of California, San Diego
  • Emory University
  • University of Freiburg
  • University of California Los Angeles
  • Translational Genomics Research Institute
  • Hospital Universitario de Valme
  • University of Zurich
  • Portland VA Medical Center
  • University of Toulouse
  • Newcastle University
  • German Center for Neurodegenerative Diseases
  • Cleveland Clinic
  • University of Manchester
  • University of Michigan–Ann Arbor
  • Helmholtz Zentrum München
  • Ludwig Maximilian University of Munich
  • University of Nottingham
  • Leipzig University
  • University of Aveiro
  • National Institutes of Health
  • University of Florence
  • University of Colorado Anschutz Medical Campus
  • University of Bristol
  • Duke Medical Center
  • University of North Carolina at Chapel Hill
  • Oregon Health & Science University
  • National Institute of Neurological Disorders and Stroke
  • Ente Ospedaliero Ospedali Galliera
  • Centro de Biología Molecular Severo Ochoa
  • Columbia University Medical Center
  • Wellcome Sanger Institute
  • University of Montpellier
  • Utah State University
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41588-019-0358-2

    DOI

    http://dx.doi.org/10.1038/s41588-019-0358-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112439232

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30820047


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