New insights on the genetic etiology of Alzheimer’s and related dementia
Céline Bellenguez(Inserm), Fahri Küçükali(University of Antwerp), Iris E. Jansen(Amsterdam Neuroscience), Víctor Andrade(University of Cologne), Sonia Moreno–Grau(Instituto de Salud Carlos III), Najaf Amin(Erasmus MC), Adam C. Naj(Genomics (United Kingdom)), Benjamin Grenier‐Boley(Inserm), Rafael Campos-Martín(University of Cologne), Peter Holmans(Cardiff University), Anne Boland(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Luca Kleineidam(University of Cologne), Vincent Damotte(Inserm), Sven J. van der Lee(Amsterdam Neuroscience), Teemu Kuulasmaa(University of Eastern Finland), Qiong Yang(Boston University), Itziar de Rojas(Instituto de Salud Carlos III), Joshua C. Bis(University of Washington), Amber Yaqub(Erasmus MC), Ivana Nedeljković(Erasmus MC), Marcos R. Costa(Inserm), Julien Chapuis(Inserm), Shahzad Ahmad(Leiden University Medical Center), Vilmantas Giedraitis(Uppsala University), Merçé Boada(Instituto de Salud Carlos III), Dag Aarsland(King's College London), Pablo García‐González(Instituto de Salud Carlos III), Carla Abdelnour(Instituto de Salud Carlos III), Emilio Alarcón‐Martín(Fundació ACE), Montserrat Alegret(Instituto de Salud Carlos III), Ignacio Álvarez(Hospital Terrassa), Victoria Álvarez(Instituto de Investigación Biosanitaria de Granada), Nicola J. Armstrong(UNSW Sydney), Anthoula Tsolaki(Aristotle University of Thessaloniki), Carmen Antúnez(Hospital Universitario Virgen de la Arrixaca), Ildebrando Appollonio(Azienda Ospedaliera San Gerardo), Marina Arcaro(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Silvana Archetti(University of Brescia), Alfonso Arias Pastor(Hospital Universitari de Santa Maria), Beatrice Arosio(University of Milan), Lavinia Athanasiu(University of Oslo), Henri Bailly(Université Paris Cité), Nerisa Banaj(Fondazione Santa Lucia), Miquel Baquero(Hospital Universitari i Politècnic La Fe), Ana Belén Pastor(Fundacion Centro De Investigacion De Enfermedades Neurologicas), Luisa Benussi(Centro San Giovanni di Dio Fatebenefratelli), Claudine Berr(Inserm), Céline Besse(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Valentina Bessi(Azienda Ospedaliero-Universitaria Careggi), Giuliano Binetti(Centro San Giovanni di Dio Fatebenefratelli), Alessandra Bizzarro(Agostino Gemelli University Polyclinic), Daniel Alcolea(Instituto de Salud Carlos III), Rafael Blesa(Instituto de Salud Carlos III), Barbara Borroni(University of Brescia), Silvia Boschi(University of Turin), Paola Bossù(Fondazione Santa Lucia), Geir Bråthen(Norwegian University of Science and Technology), Catherine Bresner(Cardiff University), Keeley J. Brookes(Nottingham Trent University), Luis Ignacio Brusco(Universidad de Buenos Aires), Katharina Bürger(German Center for Neurodegenerative Diseases), María J. Bullido(Instituto de Salud Carlos III), Vanessa Burholt(University of Auckland), William S. Bush(Case Western Reserve University), Miguel Calero(Instituto de Salud Carlos III), Carole Dufouil(Université de Bordeaux), Ãngel Carracedo(Universidade de Santiago de Compostela), Roberta Cecchetti(University of Perugia), Laura Cervera‐Carles(Instituto de Salud Carlos III), Camille Charbonnier(Inserm), Caterina Chillotti(University of Cagliari), Henry Brodaty(UNSW Sydney), Simona Ciccone(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Jurgen A.H.R. Claassen(Radboud University Nijmegen), Christopher Clark(Cardiff University), Elisa Conti(University of Milano-Bicocca), Anaïs Corma‐Gómez(Hospital Universitario de Valme), Emanuele Maria Costantini(Agostino Gemelli University Polyclinic), Carlo Custodero(University of Bari Aldo Moro), Delphine Daian(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Carolina Dalmasso(University of Cologne), Antonio Daniele(Agostino Gemelli University Polyclinic), Efthimios Dardiotis(University of Thessaly), Jean‐François Dartigues(Inserm), Peter Paul De Deyn(University Medical Center Groningen), Kátia de Paiva Lopes(Allen Institute for Brain Science), Lot D. de Witte(Icahn School of Medicine at Mount Sinai), Stéphanie Debette(Université de Bordeaux), Jürgen Deckert, Teodoro del Ser(Fundacion Centro De Investigacion De Enfermedades Neurologicas), Nicola Denning(Cardiff University), Anita L. DeStefano(Boston University), Martin Dichgans(German Center for Neurodegenerative Diseases), Janine Diehl‐Schmid(TUM Klinikum), Mónica Díez-Fairén(Hospital Terrassa), Paolo Rossi(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Srdjan Djurovic(University of Oslo), Emmanuelle Duron(Université Paris Cité), Emrah Düzel(German Center for Neurodegenerative Diseases), Sebastiaan Engelborghs(Vrije Universiteit Brussel), Valentina Escott‐Price(Instituto de Salud Carlos III), Ana Espinosa(Instituto de Salud Carlos III), Dolores Buiza‐Rueda(Instituto de Salud Carlos III), Michael Ewers(Instituto de Salud Carlos III), Fabrizio Tagliavini(Instituto de Salud Carlos III), Sune Fallgaard Nielsen(Instituto de Salud Carlos III), Lucia Farotti(University of Perugia), Chiara Fenoglio(University of Milan), Marta Fernández‐Fuertes(Hospital Universitario de Valme), John Hardy(Texas Tech University), Raffaele Ferrari(Texas Tech University), Catarina B. Ferreira(University of Lisbon), Evelyn Ferri(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Bertrand Fin(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Peter Fischer(Erasmus MC), Tormod Fladby(University of Oslo), Klaus Fließbach(University Hospital Bonn), Juan Fortea(Instituto de Salud Carlos III), Silvia Fostinelli(Centro San Giovanni di Dio Fatebenefratelli), Nick C. Fox(UK Dementia Research Institute), Emlio Franco-Macías(Instituto de Biomedicina de Sevilla), Ana Frank(Hospital Universitario La Paz), Lutz Froelich(Heidelberg University), Daniela Galimberti(University of Milan), José María García‐Alberca(Instituto de Salud Carlos III), Sebastián García‐Madrona(University of Eastern Finland), Guillermo García‐Ribas(Instituto Ramón y Cajal de Investigación Sanitaria), Geneviève Chêne(Université de Bordeaux), Roberta Ghidoni(Centro San Giovanni di Dio Fatebenefratelli), Ina Giegling(Boston University), Giorgio Giaccone(Instituto de Salud Carlos III), Oliver Goldhardt(TUM Klinikum), Antonio González-Pérez(Centro Andaluz de Biología del Desarrollo), Caroline Graff(Karolinska University Hospital), Giulia Grande(Stockholm University), Emma Green(University of Cambridge), Timo Grimmer(TUM Klinikum), Edna Grünblatt(University of Zurich), Tamar Guetta‐Baranes(University of Nottingham), Annakaisa Haapasalo(Shiga University), Georgios M. Hadjigeorgiou(University of Cyprus), Jonathan L. Haines(Case Western Reserve University), Kara L. Hamilton‐Nelson(University of Miami), EADB(Aristotle University of Thessaloniki), Gra@ce, ADGC(Boston University), Charge(German Center for Neurodegenerative Diseases), DemGen(Cardiff University), FinnGen(Genomics (United Kingdom)), EADI(Genomics (United Kingdom)), GERAD(University Hospital Bonn), Harald Hampel(Instituto de Salud Carlos III), Olivier Hanon, Annette M. Hartmann(Boston University), Lucrezia Hausner(German Center for Neurodegenerative Diseases), Janet Harwood(Amsterdam Neuroscience), Stefanie Heilmann‐Heimbach(Genomics (United Kingdom)), Seppo Helisalmi(Inserm), Michael T. Heneka, Isabel Hernández(Genomics (United Kingdom)), Martin J. Herrmann(University of Washington), Per Hoffmann(Genomics (United Kingdom)), Clive Holmes(Stavanger University Hospital), Henne Holstege(University of Washington), Raquel Huerto Vilas(Genomics (United Kingdom)), Marc Hulsman(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Jack Humphrey(Genomics (United Kingdom)), Geert Jan Biessels(Cardiff University), Charlotte Johansson(University of Washington), Patrick G. Kehoe(University of Oxford), Lena Kilander(Stavanger University Hospital), Anne Kinhult Ståhlbom(Universidade Federal do Rio Grande do Norte), Miia Kivipelto(Agostino Gemelli University Polyclinic), Anne M. Koivisto(Amsterdam Neuroscience), Johannes Kornhuber(Genomics (United Kingdom)), Mary H. Kosmidis(Framingham Heart Study), Pavel P. Kuksa(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Brian W. Kunkle(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Carmen Lage(Fundació ACE), Erika J. Laukka(University of Washington), Alessandra Lauria, Chien‐Yueh Lee(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Jenni Lehtisalo(Stavanger University Hospital), Claudia L. Satizábal(Framingham Heart Study), Ondřej Lerch(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Alberto Lleó(Cardiff University), Rogelio León López(University Hospital Bonn), Oscar L. López(University of Washington), Adolfo Lopez de Munain(Inserm), Seth Love(Hospital Universitario de Valme), Malin Löwemark(Cardiff University), Lauren Luckcuck(German Center for Neurodegenerative Diseases), Juan Macı́as(Universidade de Santiago de Compostela), Catherine Macleod(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Wolfgang Maier(University Hospital Bonn), Francesca Mangialasche(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Marco Spallazzi(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Marta Marquié(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Iain Marshall(Instituto de Salud Carlos III), Eden R. Martin(University of Oxford), Ángel Martín Montes(Centro San Giovanni di Dio Fatebenefratelli), Carmen Martínez Rodríguez(Université Paris Cité), Carlo Masullo(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Richard Mayeux(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Simon Mead(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Patrizia Mecocci(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Miguel Medina(Instituto de Salud Carlos III), Alun Meggy(Instituto de Salud Carlos III), Silvia Mendoza(Instituto de Salud Carlos III), Manuel Menéndez‐González(German Center for Neurodegenerative Diseases), Pablo Mir(Instituto de Salud Carlos III), María Teresa Periñán(University of Cologne), Merel O. Mol(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Laura Molina‐Porcel(German Center for Neurodegenerative Diseases), Laura Montrreal(German Center for Neurodegenerative Diseases), Laura Morelli(Instituto de Salud Carlos III), Fermín Moreno(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Kevin Morgan(Instituto de Salud Carlos III), Markus M. Nöthen, Carolina Muchnik(Instituto de Salud Carlos III), Benedetta Nacmias(German Center for Neurodegenerative Diseases), Tiia Ngandu(Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico), Gaël Nicolas(Universidade Federal do Rio Grande do Norte), Børge G. Nordestgaard(Instituto de Salud Carlos III), Robert Olaso(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Adelina Orellana(Instituto de Salud Carlos III), Michela Orsini(Fundació ACE), Gemma Ortega(Instituto de Salud Carlos III), Alessandro Padovani(German Center for Neurodegenerative Diseases), Paolo Caffarra(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Goran Papenberg(Universidade Federal do Rio Grande do Norte), Lucilla Parnetti(Instituto de Salud Carlos III), Florence Pasquier(German Center for Neurodegenerative Diseases), Pau Pástor(Hospital Terrassa), Alba Pérez‐Cordón(Amsterdam UMC Location Vrije Universiteit Amsterdam), Jordi Pérez‐Tur(Amsterdam UMC Location Vrije Universiteit Amsterdam), Pierre Péricard(German Center for Neurodegenerative Diseases), Oliver Peters(Amsterdam UMC Location Vrije Universiteit Amsterdam), Yolande A.L. Pijnenburg(Amsterdam Neuroscience), Juan A. Pineda, Gerard Piñol‐Ripoll(Case Western Reserve University), Claudia Pisanu(Instituto de Salud Carlos III), Thomas Polak(Amsterdam UMC Location Vrije Universiteit Amsterdam), Julius Popp(Amsterdam UMC Location Vrije Universiteit Amsterdam), Daniëlle Posthuma(Cognitive Research (United States)), Josef Priller(Amsterdam UMC Location Vrije Universiteit Amsterdam), Raquel Puerta(Fundació ACE), Olivier Quenez(University of Eastern Finland), Inés Quintela(Donauspital), Jesper Qvist Thomassen(University of Eastern Finland), Alberto Rábano(University of Eastern Finland), Innocenzo Rainero, Inez H.G.B. Ramakers(Aristotle University of Thessaloniki), Luís Miguel Real(University of Eastern Finland), Marcel Reinders(University of Milano-Bicocca), Steffi G. Riedel‐Heller(University of Eastern Finland), Peter Riederer(Erasmus MC), Eloy Rodríguez‐Rodríguez(University of Eastern Finland), Arvid Rongve(University of Eastern Finland), Irene Rosas Allende(Instituto de Salud Carlos III), Maitée Rosende-Roca, José Luís Royo(University of Eastern Finland), Elisa Rubino(University of Eastern Finland), Dan Rujescu(Boston University), María Eugenia Sáez(University of Eastern Finland), Paraskevi Sakka(University of Eastern Finland), Ingvild Saltvedt(University of Eastern Finland), Ángela Sanabria(Boston University), María Bernal Sánchez‐Arjona(Instituto de Salud Carlos III), Florentino Sánchez-García(Amsterdam Neuroscience), Shima Mehrabian(Boston University), Pascual Sánchez‐Juan(German Center for Neurodegenerative Diseases), Raquel Sánchez‐Valle(TUM Klinikum), Sigrid Botne Sando(German Center for Neurodegenerative Diseases), Michela Scamosci(Erasmus MC), Nikolaos Scarmeas(Boston University), Elio Scarpini(Instituto de Salud Carlos III), Philip Scheltens(Amsterdam Neuroscience), Norbert Scherbaum(Boston University), Martin Scherer(Boston University), Matthias Schmid(Boston University), Anja Schneider(German Center for Neurodegenerative Diseases), Jonathan M. Schott(Genomics (United Kingdom)), Geir Selbæk(German Center for Neurodegenerative Diseases), Jin Sha(Fundació ACE), Alexey Shadrin, Olivia Anna Skrobot(German Center for Neurodegenerative Diseases), Gijsje J. L. Snijders, Hilkka Soininen(Fundació ACE), Vincenzo Solfrizzi(Instituto de Salud Carlos III), Alina Solomon(Amsterdam Neuroscience), Sandro Sorbi, Óscar Sotolongo‐Grau(Fundació ACE), Gianfranco Spalletta(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Annika Spottke(German Center for Neurodegenerative Diseases), Alessio Squassina(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Juan Pablo Tartari(Boston University), Lluís Tárraga(University of Washington), Niccoló Tesi(Boston University), Anbupalam Thalamuthu(Instituto de Salud Carlos III), Thomas Tegos(Boston University), Latchezar Traykov(Boston University), Lucio Tremolizzo(University of Antwerp), Anne Tybjærg‐Hansen(Boston University), André G. Uitterlinden(Boston University), Abbe Ullgren(University of Antwerp), Ingun Ulstein(Boston University), Sergi Valero(Instituto de Salud Carlos III), Christine Van Broeckhoven(Case Western Reserve University), Aad van der Lugt(Boston University), Jasper Van Dongen(German Center for Neurodegenerative Diseases), Jeroen van Rooij(Boston University), John C. van Swieten(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Rik Vandenberghe(Boston University), Frans Verhey(Boston University), Jean‐Sébastien Vidal(Framingham Heart Study), Jonathan Vogelgsang(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Martin Vyhnálek(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Michael Wagner(Framingham Heart Study), David Wallon(Framingham Heart Study), Li‐San Wang(Instituto de Salud Carlos III), Ruiqi Wang(Boston University), Leonie Weinhold(Boston University), Jens Wiltfang(Framingham Heart Study), Gill Windle(Boston University), Bob Woods(University of Washington), Mary Yannakoulia(University of Washington), Yi Zhao(University of Washington), Miren Zulaica(Instituto de Salud Carlos III), Manuel Serrano‐Ríos(Framingham Heart Study), Davide Seripa(Hospital Universitario La Paz), Eystein Stordal(Erasmus MC), Lindsay A. Farrer(Instituto de Salud Carlos III), Bruce M. Psaty(University of Washington), Mohsen Ghanbari(University of Washington), Towfique Raj(University of Washington), Perminder S. Sachdev(Inserm), Karen A. Mather(Case Western Reserve University), Frank Jessen(Instituto de Salud Carlos III), M. Arfan Ikram(Instituto de Salud Carlos III), Alexandre de Mendonça(Inserm), Jakub Hort(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Magda Tsolaki(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Margaret A. Pericak‐Vance(Université de Bordeaux), Philippe Amouyel(Inserm), Julie Williams(University of Eastern Finland), Ruth Frikke‐Schmidt(University of Antwerp), Jordi Clarimón(Instituto de Salud Carlos III), Jean‐François Deleuze(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Giacomina Rossi(Instituto de Salud Carlos III), Sudha Seshadri(Amsterdam Neuroscience), Ole A. Andreassen(University of Washington), Martin Ingelsson(University of Cologne), Mikko Hiltunen(Inserm), Kristel Sleegers, Gerard D. Schellenberg(Cardiff University), Cornelia M. van Duijn(Erasmus MC), Rebecca Sims(Cardiff University), Wiesje M. van der Flier(Amsterdam Neuroscience), Agustı́n Ruiz(Instituto de Salud Carlos III), Alfredo Ramı́rez, Jean‐Charles Lambert(Inserm)
Cited by 90Open Access
Abstract
ABSTRACT Alzheimer’s disease (AD) is a severe and incurable neurodegenerative disease, and the failure to find effective treatments suggests that the underlying pathology remains poorly understood. Due to its strong heritability, deciphering the genetic landscape of AD and related dementia (ADD) is a unique opportunity to advance our knowledge. We completed a meta-analysis of genome-wide association studies (39,106 clinically AD-diagnosed cases, 46,828 proxy-ADD cases and 401,577 controls) with the most promising signals followed-up in 25,392 independent AD cases and 276,086 controls. We report 75 risk loci for ADD, including 42 novel ones. Pathway-enrichment analyses confirm the involvement of amyloid/Tau pathways, highlight the role of microglia and its potential interaction with APP metabolism. Numerous genes exhibited differential expression or splicing in AD-related conditions and gene prioritization implies EGFR signaling and TNF-α pathway through LUBAC complex. We also generated a novel polygenic risk score strongly associated with the risk of future dementia or progression from mild cognitive impairment to dementia. In conclusion, by more than doubling the number of loci associated with ADD risk, our study offers new insights into the pathophysiological processes underlying AD and offers additional therapeutic entry-points and tools for translational genomics.
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