Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
Valentina Escott‐Price(Cardiff University), Céline Bellenguez(Inserm), Li‐San Wang(University of Pennsylvania), Seung‐Hoan Choi(Boston University), Denise Harold(Cardiff University), Lesley Jones(Cardiff University), Peter Holmans(Cardiff University), Amy Gerrish(Cardiff University), Alexey Vedernikov(Cardiff University), Alexander Richards(Cardiff University), Anita L. DeStefano(Boston University), Jean‐Charles Lambert(Inserm), Carla A. Ibrahim‐Verbaas(Erasmus MC), Adam C. Naj(University of Pennsylvania), Rebecca Sims(Cardiff University), Gyungah Jun(Boston University), Joshua C. Bis(University of Washington), Gary W. Beecham(University of Miami), Benjamin Grenier‐Boley(Inserm), Giancarlo Russo(University of Zurich), Tricia A. Thornton‐Wells(Vanderbilt University), Nicola Denning(Cardiff University), Albert V. Smith(University of Iceland), Vincent Chouraki(Boston University), Charlene Thomas(Cardiff University), M. Arfan Ikram(Erasmus MC), Diana Zélénika, Badri N. Vardarajan(Boston University), Yoichiro Kamatani(Fondation Jean Dausset-CEPH), Chiao‐Feng Lin(University of Pennsylvania), Helena Schmidt(Medical University of Graz), Brian W. Kunkle(University of Miami), Melanie Dunstan(Cardiff University), Maria Vronskaya(Cardiff University), Andrew D. Johnson(Framingham Heart Study), Agustı́n Ruiz(Fundació ACE), Marie‐Thérèse Bihoreau, Christiane Reitz(Columbia University), Florence Pasquier(Université de Lille), Paul Hollingworth(Cardiff University), Olivier Hanon(Université Paris Cité), Annette L. Fitzpatrick(University of Washington), Joseph D. Buxbaum(Icahn School of Medicine at Mount Sinai), Dominique Campion(Inserm), Paul K. Crane(University of Washington), Clinton T. Baldwin(Boston University), Tim Becker(University of Bonn), Vilmundur Guðnason(University of Iceland), Carlos Cruchaga(Hope Center for Neurological Disorders), David Craig(Queen's University Belfast), Najaf Amin(Erasmus MC), Claudine Berr(Inserm), Oscar L. Lopez(University of Pittsburgh), Philip L. De Jager(Broad Institute), Vincent Deramecourt(Université de Lille), Janet Johnston(Queen's University Belfast), Denis A. Evans(Rush University Medical Center), Simon Lovestone(King's College London), Luc Letenneur(Inserm), Isabel Hernández(Fundació ACE), David C. Rubinsztein(University of Cambridge), Gudny Eiriksdottir(Icelandic Heart Association), Kristel Sleegers(University of Antwerp), Alison Goate(Hope Center for Neurological Disorders), Nathalie Fiévet(Inserm), Matthew J. Huentelman(Translational Genomics Research Institute), Michael Gill(Trinity College Dublin), Kristelle Brown(University of Nottingham), M. Ilyas Kamboh(University of Pittsburgh), Lina Keller(Stockholm University), Pascale Barberger‐Gateau(King's College London), Bernadette McGuinness(Queen's University Belfast), Eric B. Larson(Group Health Cooperative), Amanda Myers(University of Miami), Carole Dufouil(Inserm), Stephen Todd(Queen's University Belfast), David Wallon(Inserm), Seth Love(Frenchay Hospital), Ekaterina Rogaeva(University of Toronto), John Gallacher(University Hospital of Wales), Peter St George‐Hyslop(University of Toronto), Jordi Clarimón(Universitat Autònoma de Barcelona), Alberto Lleó(Universitat Autònoma de Barcelona), Anthony Bayer(University Hospital of Wales), Debby W. Tsuang(University of Washington), Lei Yu(Rush University Medical Center), Magda Tsolaki(Aristotle University of Thessaloniki), Paola Bossù(Fondazione Santa Lucia), Gianfranco Spalletta(Fondazione Santa Lucia), Petra Proitsi(King's College London), John Collinge(MRC Prion Unit), Sandro Sorbi(University of Florence), Florentino Sánchez-García(Hospital Universitario de Gran Canaria Doctor Negrín), Nick C. Fox(UK Dementia Research Institute), John Hardy, María Cándida Déniz Naranjo(Hospital Universitario de Gran Canaria Doctor Negrín), Paolo Bosco(Oasi Maria SS), Robert Clarke(University of Oxford), Carol Brayne(University of Cambridge), Daniela Galimberti(University of Milan), Elio Scarpini(University of Milan), Ubaldo Bonuccelli(University of Pisa), Michelangelo Mancuso(University of Pisa), Gabriele Siciliano(University of Pisa), Susanne Moebus(Institut für Medizinische Informatik, Biometrie und Epidemiologie), Patrizia Mecocci(University of Perugia), Maria Del Zompo(University of Cagliari), Wolfgang Maier(University of Bonn), Harald Hampel(Goethe University Frankfurt), Alberto Pilotto(Casa Sollievo della Sofferenza), Ana Frank(Biomedical Research Networking Center on Neurodegenerative Diseases), Francesco Panza(University of Bari Aldo Moro), Vincenzo Solfrizzi(University of Bari Aldo Moro), Paolo Caffarra(University of Parma), Benedetta Nacmias(University of Florence), William Perry(University of Miami), Manuel Mayhaus(Saarland University), Lars Lannfelt(Uppsala University), Håkon Håkonarson(Children's Hospital of Philadelphia), Sabrina Pichler(Saarland University), Minerva M. Carrasquillo(Mayo Clinic in Florida), Martin Ingelsson(Uppsala University), Duane Beekly(University of Washington), Victoria Álvarez(Universidad de Oviedo), Fanggeng Zou(Mayo Clinic in Florida), Otto Valladares(University of Pennsylvania), Steven G. Younkin(Mayo Clinic in Florida), Eliécer Coto(Universidad de Oviedo), Kara L. Hamilton‐Nelson(University of Miami), Wei Gu(Saarland University), Cristina Razquín(Universidad de Navarra), Pau Pástor(Instituto de Salud Carlos III), Ignacio Mateo(Universidad de Cantabria), Michael J. Owen(Cardiff University), Kelley M. Faber(Indiana University – Purdue University Indianapolis), Pálmi V. Jónsson(Reykjavík University), Onofre Combarros(Universidad de Cantabria), Michael O‘Donovan(Cardiff University), Laura B. Cantwell(University of Pennsylvania), Hilkka Soininen(University of Eastern Finland), Deborah Blacker(Massachusetts Department of Public Health), Simon Mead(MRC Prion Unit), Thomas H. Mosley(University of Mississippi Medical Center), David A. Bennett(Rush University Medical Center), Tamara B. Harris, Laura Fratiglioni(Karolinska University Hospital), Clive Holmes(University of Southampton), Renée F.A.G. de Bruijn(Erasmus MC), Peter Passmore(Queen's University Belfast), Thomas J. Montine(University of Washington), Karolien Bettens(University of Antwerp), Jerome I. Rotter(The Lundquist Institute), Alexis Brice(Centre National de la Recherche Scientifique), Kevin Morgan(University of Nottingham), Tatiana Foroud(Indiana University – Purdue University Indianapolis), Walter A. Kukull(University of Washington), Didier Hannequin(Inserm), John Powell(King's College London), Michael A. Nalls(National Institute on Aging), Karen Ritchie(Inserm), Kathryn L. Lunetta(Boston University), John S.K. Kauwe(Brigham Young University), Eric Boerwinkle(Baylor College of Medicine), Matthias Riemenschneider(Saarland University), Merçé Boada(Universitat Autònoma de Barcelona), Mikko Hiltunen(University of Eastern Finland), Eden R. Martin(University of Miami), Reinhold Schmidt(Medical University of Graz), Dan Rujescu(Ludwig-Maximilians-Universität München), Jean‐François Dartigues(Inserm), Richard Mayeux(Columbia University), Christophe Tzourio(Inserm), Albert Hofman(Erasmus MC), Markus M. Nöthen(University of Bonn), Caroline Graff(Karolinska University Hospital), Bruce M. Psaty(Group Health Cooperative), Jonathan L. Haines(Vanderbilt University), Mark Lathrop(Boston University), Margaret A. Pericak‐Vance(University of Miami), Lenore J. Launer, Christine Van Broeckhoven(University of Antwerp), Lindsay A. Farrer(Boston University), Cornelia M. van Duijn(Erasmus MC), Alfredo Ramı́rez(University of Bonn), Sudha Seshadri(Boston University), Gerard D. Schellenberg(University of Pennsylvania), Philippe Amouyel(Inserm), Julie Williams(Cardiff University)
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Abstract
BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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