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

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

Collaborators (186)

Jones L1, Lambert JC2, Wang LS3, Choi SH4, Harold D5, Vedernikov A1, Escott-Price V1, Stone T1, Richards A1, Bellenguez C2, Ibrahim-Verbaas CA6, Naj AC7, Sims R1, Gerrish A1, Jun G8, DeStefano AL4, Bis JC9, Beecham GW10, Grenier-Boley B2, Russo G11, Thornton-Wells TA12, Jones N1, Smith AV13, Chouraki V2, Thomas C1, Ikram MA14, Zelenika D15, Vardarajan BN16, Kamatani Y17, Lin CF3, Schmidt H18, Kunkle BW7, Dunstan ML1, Ruiz A19, Bihoreau MT15, Reitz C20, Pasquier F21, Hollingworth P1, Hanon O22, Fitzpatrick AL23, Buxbaum JD24, Campion D25, Crane PK26, Becker T27, Gudnason V13, Cruchaga C28, Craig D29, Amin N30, Berr C31, Lopez OL32, De Jager PL33, Deramecourt V34, Johnston JA29, Evans D35, Lovestone S36, Letteneur L37, Kornhuber J38, Tárraga L19, Rubinsztein DC39, Eiriksdottir G40, Sleegers K41, Goate AM28, Fiévet N42, Huentelman MJ43, Gill M44, Emilsson V13, Brown K45, Kamboh MI46, Keller L47, Barberger-Gateau P37, McGuinness B29, Larson EB48, Myers AJ49, Dufouil C37, Todd S29, Wallon D25, Love S50, Kehoe P50, Rogaeva E51, Gallacher J52, St George-Hyslop P53, Clarimon J54, Lleò A54, Bayer A52, Tsuang DW55, Yu L56, Tsolaki M57, Bossù P58, Spalletta G58, Proitsi P36, Collinge J59, Sorbi S60, Sanchez Garcia F61, Fox N62, Hardy J63, Deniz Naranjo MC61, Razquin C64, Bosco P65, Clarke R66, Brayne C67, Galimberti D68, Mancuso M69, Moebus S70, Mecocci P71, Del Zompo M72, Maier W73, Hampel H74, Pilotto A75, Bullido M76, Panza F77, Caffarra P78, Nacmias B60, Gilbert JR10, Mayhaus M79, Jessen F73, Dichgans M80, Lannfelt L81, Hakonarson H82, Pichler S79, Carrasquillo MM83, Ingelsson M81, Beekly D84, Alavarez V85, Zou F83, Valladares O3, Younkin SG83, Coto E85, Hamilton-Nelson KL7, Mateo I86, Owen MJ1, Faber KM87, Jonsson PV88, Combarros O86, O'Donovan MC1, Cantwell LB3, Soininen H89, Blacker D90, Mead S59, Mosley TH Jr91, Bennett DA92, Harris TB93, Fratiglioni L94, Holmes C95, de Bruijn RF96, Passmore P29, Montine TJ97, Bettens K41, Rotter JI98, Brice A99, Morgan K45, Foroud TM87, Kukull WA100, Hannequin D25, Powell JF36, Nalls MA101, Ritchie K31, Lunetta KL4, Kauwe JS39, Boerwinkle E102, Riemenschneider M103, Boada M104, Hiltunen M89, Martin ER10, Pastor P105, Schmidt R106, Rujescu D107, Dartigues JF108, Mayeux R20, Tzourio C109, Hofman A14, Nöthen MM110, Graff C111, Psaty BM112, Haines JL113, Lathrop M114, Pericak-Vance MA10, Launer LJ93, Farrer LA115, van Duijn CM30, Van Broeckhoven C41, Ramirez A116, Schellenberg GD3, Seshadri S117, Amouyel P118, Williams J119, Holmans PA1.

Author information

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

PMID:
25533204
PMCID:
PMC4672734
DOI:
10.1016/j.jalz.2014.05.1757
[Indexed for MEDLINE]
Free PMC Article

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