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

Nature Genetics · 2019 · Vol. 51(3) · pp. 414–430

Brian W. Kunkle✉(University of Miami)The European Alzheimer’s Disease Initiative (EADI),(Inserm)Benjamin Grenier‐Boley(Inserm)Rebecca Sims(University of Washington)Joshua C. Bis(Inserm)Vincent Damotte(Inserm)Adam C. Naj(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Anne Boland(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Maria Vronskaya(Erasmus MC)Sven J. van der Lee(Erasmus MC)Alexandre Amlie‐Wolf(Inserm)Céline Bellenguez(Inserm)Aura Frizatti(Institut Pasteur de Lille)Vincent Chouraki(Boston University)Eden R. Martin(University of Miami)Kristel Sleegers(University of Antwerp)Nandini Badarinarayan(Icelandic Heart Association)Jóhanna Jakobsdóttir(University of Miami)Kara L. Hamilton‐Nelson(University of Miami)Sonia Moreno–Grau(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Robert Olaso(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Rachel Raybould(Boston University)Yuning Chen(Boston University)Amanda B Kuzma(University of Eastern Finland)Mikko Hiltunen(University of Eastern Finland)Taniesha Morgan(Erasmus MC)Shahzad Ahmad(Erasmus MC)Badri N. Vardarajan(Inserm)Jacques Epelbaum(University of Bonn)Per Hoffmann(University of Bonn)Merçé Boada(University of Miami)Gary W. Beecham(University of Miami)Jean-Guillaume Garnier(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Denise Harold(University of Washington)Annette L. Fitzpatrick(University of Washington)Otto Valladares(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Marie-Laure Moutet(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Amy Gerrish(University of Michigan)Albert V. Smith(University of Iceland)Liming Qu(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Delphine Bacq(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Nicola Denning(UK Dementia Research Institute)Xueqiu Jian(Brown Foundation)Yi Zhao(University of Cagliari)Maria Del Zompo(University of Cagliari)Nick C. Fox(Fundació ACE)Seung‐Hoan Choi(Universidad de Cantabria)Ignacio Mateo(Universidad de Cantabria)Joseph T. Hughes(King's College London)Hieab H.H. Adams(Erasmus MC)John Malamon(Hospital Universitario de Gran Canaria Doctor Negrín)Florentino Sánchez-García(King's College London)Yogen Patel(King's College London)Jennifer A. Brody(University of Washington)Beth A. Dombroski(Hospital Universitario de Gran Canaria Doctor Negrín)María Cándida Déniz Naranjo(Aristotle University of Thessaloniki)Makrina Daniilidou(Aristotle University of Thessaloniki)Guðný Eiríksdóttir(University of Washington)Shubhabrata Mukherjee(Inserm)David Wallon(Inserm)James Uphill(MRC Prion Unit)Thor Aspelund(University of Iceland)Laura B. Cantwell(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Fabienne Garzia(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Daniela Galimberti(University of Milan)Edith Hofer(Medical University of Graz)Mariusz Butkiewicz(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Bertrand Fin(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Elio Scarpini(Boston University)Chloé Sarnowski(Boston University)William S. Bush(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Stéphane Meslage(Friedrich-Alexander-Universität Erlangen-Nürnberg)Johannes Kornhuber(Broad Institute)Charles C. White(Broad Institute)Yeunjoo E. Song(University of North Texas)Robert C. Barber(University of North Texas)Sebastiaan Engelborghs(University of Antwerp)Sabrina Sordon(Erasmus MC)Dina Voijnovic(Erasmus MC)Perrie M. Adams(The University of Texas Southwestern Medical Center)Rik Vandenberghe(Saarland University)Manuel Mayhaus(Saarland University)L. Adrienne Cupples(Boston University)Marilyn S. Albert(Johns Hopkins University)Peter Paul De Deyn(University of Antwerp)Wei Gu(Saarland University)J.J. Himali(Boston University)Duane Beekly(University of Cagliari)Alessio Squassina(University of Cagliari)Annette M. Hartmann(Fundació ACE)Adelina Orellana(Harvard University)Deborah Blacker(Universidad de Cantabria)Eloy Rodríguez‐Rodríguez(Universidad de Cantabria)Simon Lovestone(University of Oxford)Melissa E. Garcia(Baylor College of Medicine)Rachelle S. Doody(Baylor College of Medicine)Carmen Munoz-Fernadez(Hospital Universitario de Gran Canaria Doctor Negrín)Rebecca Sussams(Boston University)Honghuang Lin(Boston University)Thomas Fairchild(University of North Texas)Yolanda A. Benito(Hospital Universitario de Gran Canaria Doctor Negrín)Clive Holmes(Erasmus MC)Hata Karamujić‐Čomić(Erasmus MC)Matthew P. Frosch(Karolinska University Hospital)Håkan Thonberg(Karolinska University Hospital)Wolfgang Maier(University of Bonn)Gennady V. Roshchupkin(Erasmus MC)Bernardino Ghetti(Uppsala University)Vilmantas Giedraitis(Uppsala University)Amit Kawalia(Boston University)Shuo Li(Boston University)Ryan Huebinger(Uppsala University)Lena Kilander(Uppsala University)Susanne Moebus(Fundació ACE)Isabel Hernández(University of Pittsburgh)M. Ilyas Kamboh(Uppsala University)RoseMarie Brundin(Uppsala University)James Turton(Boston University)Qiong Yang(Boston University)Mindy J. Katz(University of Parma)Letizia Concari(University of Parma)Jenny Lord(Boston University)Alexa S. Beiser(Boston University)C. Dirk Keene(University of Eastern Finland)Seppo Helisalmi(University of Eastern Finland)Iwona Kłoszewska(University of Washington)Walter A. Kukull(University of Eastern Finland)Anne M. Koivisto(University of Eastern Finland)Aoibhinn Lynch(Trinity College Dublin)Lluís Tárraga(Kaiser Permanente Washington Health Research Institute)Eric B. Larson(Kaiser Permanente Washington Health Research Institute)Annakaisa Haapasalo(University of Eastern Finland)Brian Lawlor(Trinity College Dublin)Sonia Thomas(Albert Einstein College of Medicine)Richard B. Lipton(Albert Einstein College of Medicine)Vincenzo Solfrizzi(Trinity College Dublin)Michael Gill(University of Washington)W. T. Longstreth(University of Washington)Thomas J. Montine(University of Washington)Vincenza Frisardi(University Hospital Mútua de Terrassa)Mónica Díez-Fairén(Erasmus MC)Fernando Rivadeneira(Erasmus MC)Ronald C. Petersen(Centre Hospitalier Universitaire de Lille)Vincent Deramecourt(Centre Hospitalier Universitaire de Lille)Ignacio Álvarez(University Hospital Mútua de Terrassa)Francesca Salani(Fondazione Santa Lucia)Antonio Ciaramella(Fondazione Santa Lucia)Eric Boerwinkle(Translational Genomics Research Institute)Eric M. Reiman(Alzheimer's Association)Nathalie Fiévet(Inserm)Jerome I. Rotter(The Lundquist Institute)Joan Reisch(Université Paris Cité)Olivier Hanon(Université Paris Cité)Chiara Cupidi(Erasmus MC)André G. Uitterlinden(Veterans Health Administration)Donald R. Royall(Université de Bordeaux)Carole Dufouil(Université de Bordeaux)Raffaele Maletta(Instituto de Salud Carlos III)Itziar de Rojas(Instituto de Salud Carlos III)Mary Sano(Centre National de la Recherche Scientifique)Alexis Brice(Centre National de la Recherche Scientifique)Roberta Cecchetti(University of Cambridge)Peter St George‐Hyslop(Inserm)Karen Ritchie(Inserm)Magda Tsolaki(Aristotle University of Thessaloniki)Debby W. Tsuang(University of Washington)Bruno Dubois(Queen's University Belfast)David Craig(Texas Tech University)Chuang‐Kuo Wu(Texas Tech University)Hilkka Soininen(University of Eastern Finland)Despoina Avramidou(Aristotle University of Thessaloniki)Roger L. Albin(Stockholm University)Laura Fratiglioni(Stockholm University)Antonia Germanou(Aristotle University of Thessaloniki)Liana G. Apostolova(Stockholm University)Lina Keller(Stockholm University)Maria Koutroumani(Aristotle University of Thessaloniki)Steven E. Arnold(University of Bari Aldo Moro)Francesco Panza(Aristotle University of Thessaloniki)Olymbia Gkatzima(University of Wisconsin–Madison)Sanjay Asthana(University of Wisconsin–Madison)Didier Hannequin(University of Miami)Patrice L. Whitehead(University of Miami)Craig Atwood(University of Pittsburgh)Paolo Caffarra(University of Nottingham)Harald Hampel(Centre National de la Recherche Scientifique)Inés Quintela(Universidade de Santiago de Compostela)Ãngel Carracedo(Uppsala University)Lars Lannfelt(Uppsala University)David C. Rubinsztein(Rush University Medical Center)Lisa L. Barnes(Rush University Medical Center)Florence Pasquier(Heidelberg University)Lutz Frölich(Heidelberg University)Sandra Barral(Queen's University Belfast)Bernadette McGuinness(Queen's University Belfast)Thomas G. Beach(Queen's University Belfast)Janet Johnston(Queen's University Belfast)James T. Becker(Queen's University Belfast)Peter Passmore(Northwestern University)Eileen H. Bigio(Northwestern University)Jonathan M. Schott(University of Washington)Thomas D. Bird(University of Washington)Jason D. Warren(Mayo Clinic in Arizona)Bradley F. Boeve(King's College London)Michelle K. Lupton(King's College London)James D. Bowen(King's College London)Petroula Proitsi(University of California, San Francisco)Adam Boxer(University of California, San Francisco)John Powell(Duke University)James R. Burke(Brigham Young University)John S.K. Kauwe(Brigham Young University)Jeffrey M. Burns(University of Pisa)Michelangelo Mancuso(University of Pisa)Joseph D. Buxbaum(University of Pisa)Ubaldo Bonuccelli(University of Pisa)Nigel J. Cairns(Washington University in St. Louis)Andrew McQuillin(University of South Florida)Chuanhai Cao(University of South Florida)Gill Livingston(University of Wisconsin–Madison)Chris Carlson(University of Wisconsin–Madison)Nicholas Bass(Fred Hutch Cancer Center)Cynthia M. Carlsson(Fred Hutch Cancer Center)John Hardy(Bruce W. Carter VA Medical Center)Regina M. Carney(Bruce W. Carter VA Medical Center)José Brás(UK Dementia Research Institute)Minerva M. Carrasquillo(UK Dementia Research Institute)Rita Guerreiro(UK Dementia Research Institute)Mariet Allen(University of Southern California)Helena C. Chui(University of Southern California)Elizabeth Fisher(Università Cattolica del Sacro Cuore)Carlo Masullo(Università Cattolica del Sacro Cuore)Elizabeth Crocco(University of Miami)Charles DeCarli(Mayo Clinic in Florida)Gina Bisceglio(University of California, Irvine)Malcolm Dick(University of California, Irvine)Li Ma(Mount Sinai Medical Center)Ranjan Duara(Mount Sinai Medical Center)Neill R. Graff‐Radford(Rush University Medical Center)Denis A. Evans(Rush University Medical Center)Angela Hodges(King's College London)Kelley M. Faber(Universität Hamburg)Martin Scherer(Universität Hamburg)Kenneth B. Fallon(University of Alabama at Birmingham)Markus J. Riemenschneider(University of Kentucky)David W. Fardo(University of Bonn)Reinhard Heun(University of Bonn)Martin R. Farlow(University of Bonn)Heike Kölsch(University of Bonn)Steven H. Ferris(University of Cologne)Markus Leber(University of Cologne)Tatiana Foroud(Indiana University School of Medicine)Isabella Heuser(University of California San Diego)Douglas Galasko(University of California San Diego)Ina Giegling(Emory University)Marla Gearing(Emory Healthcare)Michael Hüll(University of Freiburg)Daniel H. Geschwind(University of Miami)John R. Gilbert(University of Miami)John C. Morris(Brigham and Women's Hospital)Robert C. Green(Brigham and Women's Hospital)Kevin H. Mayo(Harvard University)John H. Growdon(Harvard University)Thomas Feulner(University of Pittsburgh)Ronald L. Hamilton(University of Pittsburgh)Lindy E. Harrell(University of Cologne)Dmitriy Drichel(University of Cologne)Lawrence S. Honig(UK Dementia Research Institute)Thomas D. Cushion(Translational Genomics Research Institute)Matthew J. Huentelman(Translational Genomics Research Institute)Paul Hollingworth(Duke University)Christine M. Hulette(Harvard University)Bradley T. Hyman(Harvard University)Iain Marshall(University of Washington)Gail P. Jarvik(University of Washington)Alun Meggy(University of Kentucky)Erin L. Abner(University of Kentucky)Georgina Menzies(UK Dementia Research Institute)Lee‐Way Jin(Hospital Universitario de Valme)Ganna Leonenko(Hospital Universitario de Valme)Luís Miguel Real(Boston University)Gyungah R Jun(Boston University)Clinton T. Baldwin(Boston University)Detelina Grozeva(Swedish Medical Center)Anna Karydas(University of Zurich)Giancarlo Russo(Oregon Health & Science University)Jonathan Kaye(Oregon Health & Science University)Ronald Kim(University of Bonn)Frank Jessen(Boston University)Neil W. Kowall(Boston University)Bruno Vellas(Inserm)Joel H. Kramer(University of California, San Francisco)Emma Vardy(University of California, Irvine)Frank M. LaFerla(University of California, Irvine)Karl‐Heinz Jöckel(Emory University)James J. Lah(Emory University)Martin Dichgans(Cleveland Clinic)James B. Leverenz(Cleveland Clinic)David Mann(Emory University)Allan I. Levey(Emory University)Stuart Pickering‐Brown(University of Michigan)Andrew P. Lieberman(University of Michigan)Norman Klopp(Boston University)Kathryn L. Lunetta(Boston University)H.‐Erich Wichmann(Johns Hopkins University)Constantine G. Lyketsos(University of Nottingham)Kevin Morgan(University of Nottingham)Daniel Marson(University of Nottingham)Kristelle Brown(University of Nottingham)Frank Martiniuk(University of Nottingham)Christopher Medway(University of Nottingham)Deborah C. Mash(University of Bonn)Markus M. Nöthen(University of Bonn)Eliezer Masliah(Manchester Academic Health Science Centre)Nigel M. Hooper(University of Washington)Wayne C. McCormick(Università Cattolica del Sacro Cuore)Antonio Daniele(Università Cattolica del Sacro Cuore)Susan M. McCurry(University of Washington)Antony Bayer(University of South Florida)Andrew McDavid(University of South Florida)John Gallacher(Boston University)Ann C. McKee(Boston University)Hendrik van den Bussche(Northwestern University)Marsel Mesulam(Northwestern University)Carol Brayne(University of California, San Francisco)Bruce L. Miller(University of California, San Francisco)Steffi G. Riedel‐Heller(University of Southern California)Carol A. Miller(University of Southern California)Joshua W. Miller(King's College London)Ammar Al‐Chalabi(King's College London)John C. Morris(King's College London)Christopher E. Shaw(University of Miami)Amanda Myers(University of Miami)Jens Wiltfang(University of North Texas)Sid E. O’Bryant(University of California, Davis)John Olichney(Hospital Universitario Central de Asturias)Victoria Álvarez(Mayo Clinic in Arizona)Joseph E. Parisi(National Institutes of Health)Andrew B. Singleton(National Institutes of Health)Henry L. Paulson(University of Michigan)John Collinge(University of Miami)William Perry(University of Miami)Simon Mead(University of Washington)Elaine R. Peskind(University of Washington)David H. Cribbs(University of California, Irvine)Martin N. Rossor(University of California, Irvine)Aimee Pierce(University of California, Irvine)Natalie S. Ryan(University of California, Irvine)Wayne W. Poon(University of California, Irvine)Benedetta Nacmias(University of Florence)Huntington Potter(University of Florence)Sandro Sorbi(Universität Hamburg)Joseph F. Quinn(Universität Hamburg)Eleonora Sacchinelli(University of South Florida)Ashok Raj(University of South Florida)Gianfranco Spalletta(Baylor College of Medicine)Murray A. Raskind(University of Washington)Carlo Caltagirone(Fondazione Santa Lucia)Paola Bossù(Fondazione Santa Lucia)Maria Donata Orfei(Fondazione Santa Lucia)‌Barry Reisberg(University of Oxford)Robert Clarke(University of Oxford)Christiane Reitz(John Radcliffe Hospital)A. David Smith(University of Southern California)John M. Ringman(University of Southern California)Donald Warden(John Radcliffe Hospital)Erik D. Roberson(John Radcliffe Hospital)Gordon Wilcock(University of Toronto)Ekaterina Rogaeva(University of Toronto)Amalia C. Bruni(University of California, San Francisco)Howard J. Rosen(University of California, San Francisco)Maura Gallo(The University of Texas Southwestern Medical Center)Roger N. Rosenberg(University of Bristol)Yoav Ben‐Shlomo(University of Wisconsin–Madison)Mark A. Sager(University of Wisconsin–Madison)Patrizia Mecocci(University of Perugia)Andrew J. Saykin(Mútua Terrassa)Pau Pástor(University of Miami)Michael L. Cuccaro(University of Miami)Jeffery M. Vance(Rush University Medical Center)Julie A. Schneider(University of Southern California)Lori S. Schneider(University of Southern California)Susan Slifer(University of Miami)William W. Seeley(University of California, San Francisco)Amanda Smith(University of Iceland)Joshua A. Sonnen(University of Washington)Salvatore Spina(Boston University)Robert A. Stern(Boston University)Russell H. Swerdlow(University of Kansas Medical Center)Mitchell Tang(Harvard University)Rudolph E. Tanzi(Harvard University)John Q. Trojanowski(Johns Hopkins University)Juan C. Troncoso(Johns Hopkins University)Vivianna M. Van Deerlin(University of Kentucky)Linda J. Van Eldik(University of Kentucky)Harry V. Vinters(University of California, Los Angeles)Jean Paul Vonsattel(Northwestern University)Sandra Weıntraub(Northwestern University)Kathleen A. Welsh‐Bohmer(University of North Carolina at Chapel Hill)Kirk C. Wilhelmsen(University of North Carolina at Chapel Hill)Jennifer Williamson(Emory University)Thomas S. Wingo(Emory University)Randall L. Woltjer(Oregon Health & Science University)Clinton B. Wright(University of Washington)Chang‐En Yu(Rush University Medical Center)Lei Yu(Rush University Medical Center)Yasaman Saba(Medical University of Graz)Alberto Pilotto(Casa Sollievo della Sofferenza)María J. Bullido(Instituto de Salud Carlos III)Oliver Peters(University of Washington)Paul K. Crane(Rush University Medical Center)David A. Bennett(Rush University Medical Center)Paola Bosco(Oasi Maria SS)Eliécer Coto(University of Perugia)Virginia Boccardi(University of Perugia)Phil L. De Jager(Columbia University Irving Medical Center)Alberto Lleó(Instituto de Salud Carlos III)Nicholas A. Warner(University of Pittsburgh)Lorna M. Lopez(Uppsala University)Martin Ingelsson(Uppsala University)Panos Deloukas(Washington University in St. Louis)Carlos Cruchaga(Washington University in St. Louis)Caroline Graff(Karolinska University Hospital)Rhian Gwilliam(Wellcome Sanger Institute)Myriam Fornage(Brown Foundation)Alison Goate(Universidad de Cantabria)Pascual Sánchez‐Juan(Universidad de Cantabria)Patrick G. Kehoe(Southmead Hospital)Najaf Amin(Erasmus MC)N. Ertekin-Taner(Université de Montpellier)Claudine Berr(Inserm)Stéphanie Debette(Centre National de la Recherche Scientifique)Seth Love(Southmead Hospital)Lenore J. Launer(National Institute on Aging)Steven G. Younkin(WinnMed)Jean‐François Dartigues(Utah State University)Chris Corcoran(Utah State University)M. Arfan Ikram(Erasmus MC)Dennis W. Dickson(Inserm)Gaël Nicolas(Inserm)Dominique Campion(Utah State University)JoAnn T. Tschanz(Utah State University)Helena Schmidt(Children's Hospital of Philadelphia)Håkon Håkonarson(Children's Hospital of Philadelphia)Jordi Clarimón(Utah State University)Ron Munger(Utah State University)Reinhold Schmidt(Boston University)Lindsay A. Farrer(Boston University)Christine Van Broeckhoven(University of Antwerp)Michael O’Donovan(Boston University)Anita L. DeStefano(Boston University)Lesley Jones(UK Dementia Research Institute)Jonathan L. Haines(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Jean-François Deleuze(Commissariat à l'Énergie Atomique et aux Énergies Alternatives)Michael J. Owen(University of Iceland)Vilmundur Guðnason(University of Iceland)Richard Mayeux(UK Dementia Research Institute)Valentina Escott‐Price(University of Washington)Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute)Alfredo Ramı́rez(University of Cologne)Li-San Wang(Instituto de Salud Carlos III)Agustı́n Ruiz(Instituto de Salud Carlos III)Cornelia M. van Duijn(Erasmus MC)Peter Holmans(Institute for Neurodegenerative Disorders)Sudha Seshadri(Boston University)Julie Williams(Centre Hospitalier Universitaire de Lille)Philippe Amouyel(Inserm)Gerard D. Schellenberg(Université de Lille)Jean‐Charles Lambert(University of Miami)Margaret A. Pericak‐Vance(University of Miami)

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Alzheimer's disease research and treatments Genetic Associations and Epidemiology Bioinformatics and Genomic NetworksBiologyImmunityDiseaseGeneticsAlzheimer's diseaseMeta-analysisBioinformaticsEvolutionary biologyComputational biologyImmune system

MeSH terms

AgedAlzheimer DiseaseFemaleGenetic TestingHaplotypesHumansImmunityLipidsMaleCase-Control StudiesAmyloid beta-Peptidestau ProteinsGenetic Predisposition to DiseaseLipid MetabolismGenome-Wide Association Study