Convergent genetic and expression data implicate immunity in Alzheimer's disease

International Genomics of Alzheimer's Disease Consortium (IGAP)

doi:10.1016/j.jalz.2014.05.1757

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Alzheimers Dement. 2015 Jun;11(6):658-71. doi: 10.1016/j.jalz.2014.05.1757. Epub 2014 Dec 20.

Author

International Genomics of Alzheimer's Disease Consortium (IGAP)

Collaborators

International Genomics of Alzheimer's Disease Consortium (IGAP):
Lesley Jones¹, Jean-Charles Lambert², Li-San Wang³, Seung-Hoan Choi⁴, Denise Harold⁵, Alexey Vedernikov¹, Valentina Escott-Price¹, Timothy Stone¹, Alexander Richards¹, Céline Bellenguez², Carla A Ibrahim-Verbaas⁶, Adam C Naj⁷, Rebecca Sims¹, Amy Gerrish¹, Gyungah Jun⁸, Anita L DeStefano⁴, Joshua C Bis⁹, Gary W Beecham¹⁰, Benjamin Grenier-Boley², Giancarlo Russo¹¹, Tricia A Thornton-Wells¹², Nicola Jones¹, Albert V Smith¹³, Vincent Chouraki², Charlene Thomas¹, M Arfan Ikram¹⁴, Diana Zelenika¹⁵, Badri N Vardarajan¹⁶, Yoichiro Kamatani¹⁷, Chiao-Feng Lin³, Helena Schmidt¹⁸, Brian W Kunkle⁷, Melanie L Dunstan¹, Agustin Ruiz¹⁹, Marie-Thérèse Bihoreau¹⁵, Christiane Reitz²⁰, Florence Pasquier²¹, Paul Hollingworth¹, Olivier Hanon²², Annette L Fitzpatrick²³, Joseph D Buxbaum²⁴, Dominique Campion²⁵, Paul K Crane²⁶, Tim Becker²⁷, Vilmundur Gudnason¹³, Carlos Cruchaga²⁸, David Craig²⁹, Najaf Amin³⁰, Claudine Berr³¹, Oscar L Lopez³², Philip L De Jager³³, Vincent Deramecourt³⁴, Janet A Johnston²⁹, Denis Evans³⁵, Simon Lovestone³⁶, Luc Letteneur³⁷, Johanes Kornhuber³⁸, Lluís Tárraga¹⁹, David C Rubinsztein³⁹, Gudny Eiriksdottir⁴⁰, Kristel Sleegers⁴¹, Alison M Goate²⁸, Nathalie Fiévet⁴², Matthew J Huentelman⁴³, Michael Gill⁴⁴, Valur Emilsson¹³, Kristelle Brown⁴⁵, M Ilyas Kamboh⁴⁶, Lina Keller⁴⁷, Pascale Barberger-Gateau³⁷, Bernadette McGuinness²⁹, Eric B Larson⁴⁸, Amanda J Myers⁴⁹, Carole Dufouil³⁷, Stephen Todd²⁹, David Wallon²⁵, Seth Love⁵⁰, Pat Kehoe⁵⁰, Ekaterina Rogaeva⁵¹, John Gallacher⁵², Peter St George-Hyslop⁵³, Jordi Clarimon⁵⁴, Alberti Lleò⁵⁴, Anthony Bayer⁵², Debby W Tsuang⁵⁵, Lei Yu⁵⁶, Magda Tsolaki⁵⁷, Paola Bossù⁵⁸, Gianfranco Spalletta⁵⁸, Petra Proitsi³⁶, John Collinge⁵⁹, Sandro Sorbi⁶⁰, Florentino Sanchez Garcia⁶¹, Nick Fox⁶², John Hardy⁶³, Maria Candida Deniz Naranjo⁶¹, Cristina Razquin⁶⁴, Paola Bosco⁶⁵, Robert Clarke⁶⁶, Carol Brayne⁶⁷, Daniela Galimberti⁶⁸, Michelangelo Mancuso⁶⁹, Susanne Moebus⁷⁰, Patrizia Mecocci⁷¹, Maria Del Zompo⁷², Wolfgang Maier⁷³, Harald Hampel⁷⁴, Alberto Pilotto⁷⁵, Maria Bullido⁷⁶, Francesco Panza⁷⁷, Paolo Caffarra⁷⁸, Benedetta Nacmias⁶⁰, John R Gilbert¹⁰, Manuel Mayhaus⁷⁹, Frank Jessen⁷³, Martin Dichgans⁸⁰, Lars Lannfelt⁸¹, Hakon Hakonarson⁸², Sabrina Pichler⁷⁹, Minerva M Carrasquillo⁸³, Martin Ingelsson⁸¹, Duane Beekly⁸⁴, Victoria Alavarez⁸⁵, Fanggeng Zou⁸³, Otto Valladares³, Steven G Younkin⁸³, Eliecer Coto⁸⁵, Kara L Hamilton-Nelson⁷, Ignacio Mateo⁸⁶, Michael J Owen¹, Kelley M Faber⁸⁷, Palmi V Jonsson⁸⁸, Onofre Combarros⁸⁶, Michael C O'Donovan¹, Laura B Cantwell³, Hilkka Soininen⁸⁹, Deborah Blacker⁹⁰, Simon Mead⁵⁹, Thomas H Mosley Jr⁹¹, David A Bennett⁹², Tamara B Harris⁹³, Laura Fratiglioni⁹⁴, Clive Holmes⁹⁵, Renee F A G de Bruijn⁹⁶, Peter Passmore²⁹, Thomas J Montine⁹⁷, Karolien Bettens⁴¹, Jerome I Rotter⁹⁸, Alexis Brice⁹⁹, Kevin Morgan⁴⁵, Tatiana M Foroud⁸⁷, Walter A Kukull¹⁰⁰, Didier Hannequin²⁵, John F Powell³⁶, Michael A Nalls¹⁰¹, Karen Ritchie³¹, Kathryn L Lunetta⁴, John S K Kauwe³⁹, Eric Boerwinkle¹⁰², Matthias Riemenschneider¹⁰³, Mercè Boada¹⁰⁴, Mikko Hiltunen⁸⁹, Eden R Martin¹⁰, Pau Pastor¹⁰⁵, Reinhold Schmidt¹⁰⁶, Dan Rujescu¹⁰⁷, Jean-François Dartigues¹⁰⁸, Richard Mayeux²⁰, Christophe Tzourio¹⁰⁹, Albert Hofman¹⁴, Markus M Nöthen¹¹⁰, Caroline Graff¹¹¹, Bruce M Psaty¹¹², Jonathan L Haines¹¹³, Mark Lathrop¹¹⁴, Margaret A Pericak-Vance¹⁰, Lenore J Launer⁹³, Lindsay A Farrer¹¹⁵, Cornelia M van Duijn³⁰, Christine Van Broeckhoven⁴¹, Alfredo Ramirez¹¹⁶, Gerard D Schellenberg³, Sudha Seshadri¹¹⁷, Philippe Amouyel¹¹⁸, Julie Williams¹¹⁹, Peter A Holmans¹

Affiliations

¹ Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ.
² Inserm U744, Lille, 59000, France; Université Lille 2, Lille, 59000, France; Institut Pasteur de Lille, Lille, 59000, France.
³ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
⁴ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
⁵ Neuropsychiatric Genetics Group, Department of Psychiatry, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8.
⁶ Department of Epidemiology, Clinical Genetics and Neurology, Erasmus MC University Medical Center, Rotterdam, 3015 CE, The Netherlands.
⁷ The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33124, USA.
⁸ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, 02218, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, 02215, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA.
¹⁰ The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, 33124, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, 33124, USA.
¹¹ Functional Genomics Center, Zurich, 8038, Switzerland.
¹² Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37212, USA.
¹³ University of Iceland, Faculty of Pharmaceutical Sciences, Reykjavik, 525-4000, Iceland; Icelandic Heart Association, Kopavogur, 525-4000, Iceland.
¹⁴ Departments of Epidemiology, Neurology and Radiology, Erasmus MC University Medical Center, Rotterdam, 3015 CE, The Netherlands; Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
¹⁵ Centre National de Genotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry, 91300, France.
¹⁶ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, 02218, USA.
¹⁷ Fondation Jean Dausset- CEPH, Paris, 75010, France.
¹⁸ Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, 8010, Austria.
¹⁹ Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, 8029, Spain.
²⁰ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University New York, NY, 10027, USA; Gertrude H. Sergievsky Center, Columbia University, Department of Neurology, Columbia University, New York, NY, 10027, USA.
²¹ Université Lille 2, Lille, 59000, France; Centre Hospitalier Régional Universitaire de Lille, Lille, 59000, France.
²² UMR 894 Inserm, Faculté de Médecine, Université Paris Descartes, Paris, 75014, France.
²³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA; Departments of Epidemiology and Global Health, University of Washington, Seattle, WA, 98101, USA.
²⁴ Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, 10027, USA; Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, 10027, USA; Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, 10027, USA.
²⁵ INSERM U614, Faculté de Médecine, Centre Hospitalier du Rouvray, Rouen, 76000, France.
²⁶ Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
²⁷ German Center for Neurodegenerative Diseases (DZNE, Bonn) and Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany, 53113.
²⁸ Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, 98122, USA.
²⁹ Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, BT7 1NN, UK.
³⁰ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, 3015 CE, The Netherlands.
³¹ INSERM U888, Hôpital La Colombière, Montpellier, 34000, France.
³² Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
³³ Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02215, USA; Program in Medical and Population Genetics, Broad Institute, Boston, MA, 02215, USA.
³⁴ Inserm U744, Lille, 59000, France; Centre Hospitalier Régional Universitaire de Lille, Lille, 59000, France.
³⁵ Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, 60612, USA.
³⁶ King's College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London SE5.
³⁷ Inserm U897, Victor Segalen University, F-33076, Bordeaux, 33000, France.
³⁸ Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Germany.
³⁹ Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 OXY, UK.
⁴⁰ Icelandic Heart Association, Kopavogur, 525-4000, Iceland.
⁴¹ Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, 2000, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, 2000, Belgium.
⁴² Inserm U744, Lille, 59000, France; Institut Pasteur de Lille, Lille, 59000, France.
⁴³ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
⁴⁴ Mercer's Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Dublin 8, Ireland.
⁴⁵ Institute of Genetics, Queen's Medical Centre, University of Nottingham, NG7 2UH, UK.
⁴⁶ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
⁴⁷ Aging Reasearch Center, Dept Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, 17177, Sweden.
⁴⁸ Department of Medicine, University of Washington, Seattle, WA, 98195, USA; Group Health Research Institute, Group Health, Seattle, WA, 98195, USA.
⁴⁹ Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, 33124, USA.
⁵⁰ University of Bristol, Clinical Neurosciences, Level 1 Learning and Research Building BS10 5NB.
⁵¹ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁵² Institute of Primary Care and Public Health, Cardiff University, Neuadd Meirionnydd, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK.
⁵³ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON M5S 1A1, Canada; Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 1TN, UK.
⁵⁴ Neurology Department, IIB Sant Pau, Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, 08026, Spain; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain.
⁵⁵ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
⁵⁶ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA.
⁵⁷ Aristotle University of Thessaloniki, Despere 3, Thessaloniki, 54621, Greece.
⁵⁸ Clinical and Behavioral Neurology, Fondazione Santa Lucia, Roma, 00142, Italy.
⁵⁹ MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK.
⁶⁰ Department of Neurological and Psychiatric Sciences, University of Florence, Florence, 50121, Italy; Centro di Ricerca, Trasferimento e Alta Formazione DENOTHE, University of Florence, Florence, Italy.
⁶¹ Department of Immunology, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, 35012, Spain.
⁶² Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK.
⁶³ Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, WC1N 3BG, UK.
⁶⁴ Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, 28023, Spain.
⁶⁵ IRCCS Associazione Oasi Maria SS, Troina, 94018, Italy.
⁶⁶ Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, OX1 2JD, UK.
⁶⁷ Cognitive Function and Ageing Study (CFAS), Institute of Public Health, University of Cambridge, Cambridge, CB2 1TN, UK.
⁶⁸ University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, 20122, Italy.
⁶⁹ Neurological Clinic, University of Pisa, 56126, Italy.
⁷⁰ Urban Epidemiology, Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, 45141, Germany.
⁷¹ Section of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, 06100, Italy.
⁷² Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, 09123, Italy.
⁷³ Department of Psychiatry and Psychotherapy, University of Bonn, Germany and German Center for Neurodegenerative Diseases (DZNE, Bonn), Bonn, 53113, Germany.
⁷⁴ Université Pierre et Marie Curie, Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer, Paris, France.
⁷⁵ Gerontology and Geriatrics Research Laboratory, I.R.C.C.S. Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), 71013, Italy.
⁷⁶ Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, 28046, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigación Sanitaria "Hospital la Paz" (IdIPaz), Madrid, Spain.
⁷⁷ Departement of Geriatrics, Center for Aging Brain, University of Bari, Bari, 70121, Italy.
⁷⁸ Department of Neuroscience-University of Parma, Parma, 43100, Italy; Center for Cognitive Disorders AUSL, Parma, Italy.
⁷⁹ Dept. Of Psychiatry, University Hospital, 66424, Saarland.
⁸⁰ Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany and German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, 80336, Germany.
⁸¹ Dept. of Public Health/Geriatrics, Uppsala University, Uppsala, 75312, Sweden.
⁸² Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
⁸³ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
⁸⁴ National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, 98195, USA.
⁸⁵ Genetica molecular-Huca-Oviedo, Oviedo, 33006, Spain.
⁸⁶ Neurology Service and CIBERNED, "Marqués de Valdecilla" University Hospital (University of Cantabria and IFIMAV), Santander, 39005, Spain.
⁸⁷ Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, 46202, USA.
⁸⁸ Landspitali University Hospital, Reykjavik, 543-1000, Iceland.
⁸⁹ Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, 70211, Finland; Department of Neurology, Kuopio University Hospital, FIN-70211, Kuopio, Finland.
⁹⁰ Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, 02115, USA.
⁹¹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, USA.
⁹² Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, 60612, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, 60612, USA.
⁹³ Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, MD, 20892, USA.
⁹⁴ Aging Reasearch Center, Dept Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, 11418, Sweden; Dept Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, S-14186, Stockholm.
⁹⁵ Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, SO17 1BJ, UK.
⁹⁶ Departments of Neurology and Epidemiology, Erasmus MC University Medical Center, Rotterdam, 3015 CE, The Netherlands.
⁹⁷ Department of Pathology, University of Washington, Seattle, WA, 98195, USA.
⁹⁸ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁹⁹ CRicm-UMRS975, Paris, France; AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, 75013, France.
¹⁰⁰ Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA.
¹⁰¹ Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, 20892, USA.
¹⁰² Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genetics Center and Div. of Epidemiology, University of Texas Health Sciences Center at Houston, Houston, TX, 77030, USA.
¹⁰³ Department of Psychiatry, University Hospital, 66424, Saarland.
¹⁰⁴ Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, 8029, Spain.
¹⁰⁵ Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research and Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.
¹⁰⁶ Department of Neurology, Medical University of Graz, Graz, 8010, Austria.
¹⁰⁷ Department of Psychiatry, University of Munich, Munich and University of Halle, Halle, 80336, Germany.
¹⁰⁸ Inserm U897, Victor Segalen University, F-33076, Bordeaux, 33000, France; Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France.
¹⁰⁹ Inserm U708, Victor Segalen University, F-33076, Bordeaux, 33000, France.
¹¹⁰ Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, and German Center for Neurodegenerative Diseases (DZNE, Bonn), Bonn, 53113, Germany.
¹¹¹ Karolinska Institutet, Dept Neurobiology, Care Sciences and Society, KIADRC, Novum floor 5, S14186 Stockholm, 17177, Sweden; Dept Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, S-14186, Stockholm.
¹¹² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, 98101, USA; Departments of Epidemiology and Health Services, University of Washington, Seattle, WA, USA, Group Health Research Institute, Group Health, Seattle, WA, USA.
¹¹³ Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37212, USA; Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, 37212, USA.
¹¹⁴ Centre National de Genotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry, 91300, France; Fondation Jean Dausset- CEPH, Paris, 75010, France; McGill University and Génome Québec Innovation Centre, Montreal, Canada.
¹¹⁵ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, 02218, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, 02215, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, 02118, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, 02215, USA.
¹¹⁶ Department of Psychiatry and Psychotherapy and Institute of Human Genetics, University of Bonn, Bonn, 53113, Germany.
¹¹⁷ Department of Neurology, Boston University School of Medicine, Boston, MA, 02215, USA.
¹¹⁸ Inserm U744, Lille, 59000, France; Université Lille 2, Lille, 59000, France; Institut Pasteur de Lille, Lille, 59000, France; Centre Hospitalier Régional Universitaire de Lille, Lille, 59000, France. Electronic address: philippe.amouyel@pasteur-lille.fr.
¹¹⁹ Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ. Electronic address: williamsj@cardiff.ac.uk.

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.

Keywords: ALIGATOR; Alzheimer's disease; Cholesterol metabolism; Dementia; Endocytosis; Immune response; Neurodegeneration; Pathway analysis; Ubiquitination; Weighted gene co-expression network analysis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Algorithms
Alzheimer Disease / genetics*
Alzheimer Disease / metabolism*
Brain / metabolism*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding