Convergent genetic and expression data implicate immunity in Alzheimer's disease
Lesley Jones(University of Mississippi Medical Center), Jean‐Charles Lambert(Inserm), Weixin Wang(University of Pennsylvania), Seung‐Hoan Choi(Boston University), Denise Harold(St. James's Hospital), Alexey Vedernikov(Cardiff University), Valentina Escott‐Price(Cardiff University), Timothy Stone(Cardiff University), Alexander Richards(Cardiff University), Céline Bellenguez(Inserm), Carla A. Ibrahim‐Verbaas(Erasmus MC), Adam C. Naj(University of Miami), Rebecca Sims(Cardiff University), Amy Gerrish(Cardiff University), Gyungah Jun(Boston University), Anita L. DeStefano(Boston University), Joshua C. Bis(University of Washington), Gary W. Beecham(University of Miami), Benjamin Grenier‐Boley(Inserm), Giancarlo Russo, Tricia A. Thornton‐Wells(Vanderbilt University), Nicola Jones(Cardiff University), Albert V. Smith(University of Iceland), Vincent Chouraki(Inserm), 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), Agustı́n Ruiz(Fundació ACE), Marie‐Thérèse Bihoreau, Christiane Reitz(Columbia University), Florence Pasquier(Université de Lille), Paul Hollingworth(Cardiff University), Olivier Hanon(Délégation Paris 5), 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), Tim Becker(University of Bonn), Vilmundur Guðnason(University of Iceland), Carlos Cruchaga(Hope Center for Neurological Disorders), David W. Craig(Queen's University Belfast), Najaf Amin(Erasmus MC), Claudine Berr(Inserm), Oscar L. López(University of Pittsburgh), Philip L. De Jager(Broad Institute), Vincent Deramecourt(Inserm), Janet Johnston(Queen's University Belfast), Denis A. Evans(Rush University Medical Center), Simon Lovestone, Luc Letteneur(Inserm), Johanes Kornhuber(Friedrich-Alexander-Universität Erlangen-Nürnberg), Lluís Tárraga(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), Valur Emilsson(University of Iceland), Kristelle Brown(University of Nottingham), M. Ilyas Kamboh(University of Pittsburgh), Lina Keller(Stockholm University), Pascale Barberger‐Gateau(Inserm), 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(University of Bristol), Patrick G. Kehoe(University of Bristol), Ekaterina Rogaeva(University of Toronto), John Gallacher(University Hospital of Wales), Peter St George‐Hyslop(University of Toronto), Jordi Clarimón(Universitat Autònoma de Barcelona), Alberti Lleὀ(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, 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), Cristina Razquín(Universidad de Navarra), Paola Bosco(Oasi Maria SS), Robert Clarke(University of Oxford), Carol Brayne(University of Cambridge), Daniela Galimberti(University of Milan), Michelangelo Mancuso(University of Pisa), MRC CFAS, Susanne Moebus(University of Perugia), Patrizia Mecocci(University of Cagliari), Maria Del Zompo(University of Bonn), Wolfgang Maier(University of Bonn), Harald Hampel(Casa Sollievo della Sofferenza), Alberto Pilotto(Casa Sollievo della Sofferenza), María J. Bullido(Biomedical Research Networking Center on Neurodegenerative Diseases), Francesco Panza(University of Parma), Paolo Caffarra(University of Parma), Benedetta Nacmias(University of Miami), John R. Gilbert(University of Miami), Manuel Mayhaus(University of Bonn), Frank Jessen(University of Bonn), Martin Dichgans(Uppsala University), Lars Lannfelt(Uppsala University), Håkon Håkonarson(Children's Hospital of Philadelphia), Sabrina Pichler(Mayo Clinic in Florida), Minerva M. Carrasquillo(Uppsala University), Martin Ingelsson(Uppsala University), Duane Beekly(Universidad de Oviedo), Victoria Alavarez(Mayo Clinic in Florida), Fanggeng Zou(Mayo Clinic in Florida), Otto Valladares(Mayo Clinic in Florida), Steven G. Younkin(Universidad de Oviedo), Eliécer Coto(University of Miami), Kara L. Hamilton‐Nelson(Universidad de Cantabria), Ignacio Mateo(Universidad de Cantabria), Michael J. Owen(Indiana University – Purdue University Indianapolis), Kelley M. Faber(Reykjavík University), Pálmi V. Jónsson(Reykjavík University), Onofre Combarros(Universidad de Cantabria), Michael O‘Donovan(Cardiff University), Laura B. Cantwell(University of Eastern Finland), Hilkka Soininen(Harvard University), Deborah Blacker(Harvard University), Simon Mead(Rush University Medical Center), Thomas H. Mosley(Rush University Medical Center), David Bennett(Rush University Medical Center), Tamara B. Harris(Karolinska University Hospital), Laura Fratiglioni(Karolinska University Hospital), Clive Holmes(Erasmus MC), Renée F.A.G. de Bruijn(Queen's University Belfast), Peter Passmore(Queen's University Belfast), Thomas J. Montine(University of Antwerp), Karolien Bettens(Cedars-Sinai Medical Center), Jerome I. Rotter(Cedars-Sinai Medical Center), Alexis Brice(University of Nottingham), Kevin Morgan(University of Nottingham), Tatiana Foroud(University of Washington), Walter A. Kukull(Inserm), Didier Hannequin(Inserm), John Powell(National Institute on Aging), Michael A. Nalls(Inserm), Karen Ritchie(Boston University), Kathryn L. Lunetta(Boston University), John S.K. Kauwe(Baylor College of Medicine), Eric Boerwinkle(Baylor College of Medicine), Matthias Riemenschneider(Fundació ACE), Merçé Boada(University of Eastern Finland), Mikko Hiltunen(University of Miami), Eden R. Martin(University of Miami), Pau Pástor(Medical University of Graz), Reinhold Schmidt(Medical University of Graz), Dan Rujescu(Inserm), Jean‐François Dartigues(Inserm), Richard Mayeux(Inserm), Christophe Tzourio(Inserm), Albert Hofman(University of Bonn), Markus M. Nöthen(Karolinska University Hospital), Caroline Graff(Karolinska University Hospital), Bruce M. Psaty(Vanderbilt University), Jonathan L. Haines(Vanderbilt University), Mark Lathrop(University of Miami), Margaret A. Pericak‐Vance(University of Miami), Lenore J. Launer(Boston University), Lindsay A. Farrer(Boston University), Cornelia M. van Duijn(University of Antwerp), Christine Van Broeckhoven(University of Bonn), Alfredo Ramı́rez(University of Bonn), Gerard D. Schellenberg(Boston University), Sudha Seshadri(Boston University), Philippe Amouyel(Inserm), Julie Williams(Cardiff University), Peter Holmans(Cardiff University)
Cited by 207Open Access
Abstract
BACKGROUND: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. METHODS: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. RESULTS: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10(-11)), cholesterol transport (P = 2.96 × 10(-9)), and proteasome-ubiquitin activity (P = 1.34 × 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). CONCLUSIONS: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
Related Papers
No related papers found
Powered by citation graph analysis