sg:pub.10.1038/s41588-019-0358-2 - Springer Nature SciGraph

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

VOLUME

Subjects

FOR: Genetics

FOR: Biological Sciences

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

From Grant

Further Defining The Genetic Architecture Of Alzheimer's Disease

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