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PLoS One. 2014 Jun 12;9(6):e94661. doi: 10.1371/journal.pone.0094661. eCollection 2014.

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Escott-Price V1, Bellenguez C2, Wang LS3, Choi SH4, Harold D1, Jones L1, Holmans P1, Gerrish A1, Vedernikov A1, Richards A1, DeStefano AL4, Lambert JC2, Ibrahim-Verbaas CA5, Naj AC6, Sims R1, Jun G7, Bis JC8, Beecham GW9, Grenier-Boley B2, Russo G10, Thornton-Wells TA11, Denning N1, Smith AV12, Chouraki V13, Thomas C1, Ikram MA14, Zelenika D15, Vardarajan BN16, Kamatani Y17, Lin CF3, Schmidt H18, Kunkle B19, Dunstan ML1, Vronskaya M1; United Kingdom Brain Expression Consortium, Johnson AD20, Ruiz A21, Bihoreau MT15, Reitz C22, Pasquier F23, Hollingworth P1, Hanon O24, Fitzpatrick AL25, Buxbaum JD26, Campion D27, Crane PK28, Baldwin C29, Becker T30, Gudnason V12, Cruchaga C31, Craig D32, Amin N33, Berr C34, Lopez OL35, De Jager PL36, Deramecourt V23, Johnston JA32, Evans D37, Lovestone S38, Letenneur L39, Hernández I21, Rubinsztein DC40, Eiriksdottir G41, Sleegers K42, Goate AM31, Fiévet N43, Huentelman MJ44, Gill M45, Brown K46, Kamboh MI47, Keller L48, Barberger-Gateau P38, McGuinness B32, Larson EB49, Myers AJ50, Dufouil C39, Todd S32, Wallon D27, Love S51, Rogaeva E52, Gallacher J53, George-Hyslop PS54, Clarimon J55, Lleo A55, Bayer A53, Tsuang DW56, Yu L57, Tsolaki M58, Bossù P59, Spalletta G59, Proitsi P38, Collinge J60, Sorbi S61, Garcia FS62, Fox NC63, Hardy J64, Naranjo MC62, Bosco P65, Clarke R66, Brayne C67, Galimberti D68, Scarpini E68, Bonuccelli U69, Mancuso M69, Siciliano G69, Moebus S70, Mecocci P71, Zompo MD72, Maier W73, Hampel H74, Pilotto A75, Frank-García A76, Panza F77, Solfrizzi V77, Caffarra P78, Nacmias B61, Perry W9, Mayhaus M79, Lannfelt L80, Hakonarson H81, Pichler S79, Carrasquillo MM82, Ingelsson M80, Beekly D83, Alvarez V84, Zou F82, Valladares O3, Younkin SG82, Coto E84, Hamilton-Nelson KL19, Gu W85, Razquin C86, Pastor P87, Mateo I88, Owen MJ1, Faber KM89, Jonsson PV90, Combarros O88, O'Donovan MC1, Cantwell LB3, Soininen H91, Blacker D92, Mead S60, Mosley TH Jr93, Bennett DA94, Harris TB95, Fratiglioni L96, Holmes C97, de Bruijn RF98, Passmore P32, Montine TJ99, Bettens K42, Rotter JI100, Brice A101, Morgan K46, Foroud TM89, Kukull WA102, Hannequin D27, Powell JF38, Nalls MA103, Ritchie K104, Lunetta KL4, Kauwe JS105, Boerwinkle E106, Riemenschneider M85, Boada M107, Hiltunen M91, Martin ER9, Schmidt R108, Rujescu D109, Dartigues JF110, Mayeux R22, Tzourio C111, Hofman A14, Nöthen MM112, Graff C113, Psaty BM114, Haines JL115, Lathrop M116, Pericak-Vance MA9, Launer LJ95, Van Broeckhoven C42, Farrer LA117, van Duijn CM118, Ramirez A119, Seshadri S120, Schellenberg GD3, Amouyel P121, Williams J1; Cardiovascular Health Study (CHS).

Author information

1
Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Cardiff, United Kingdom.
2
Inserm U744, Lille, France; Université Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
4
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
5
Department of Epidemiology and Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
6
Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
7
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, United States of America; Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
8
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
9
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, United States of America.
10
Functional Genomics Center Zurich, ETH/University of Zurich, Zurich, Switzerland.
11
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
12
University of Iceland, Faculty of Medicine, Reykjavik, Iceland; Icelandic Heart Association, Kopavogur, Iceland.
13
Inserm U744, Lille, France; Université Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
14
Departments of Epidemiology, Neurology and Radiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Leiden, The Netherlands.
15
Centre National de Genotypage, Institut Genomique, Commissariat à l'énergie Atomique, Evry, France.
16
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, United States of America; Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University New York, New York, United States of America; Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, New York, United States of America.
17
Fondation Jean Dausset- CEPH, Paris, France.
18
Institute for Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
19
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
20
NHLBI Cardiovascular Epidemiology and Human Genomics Branch, The Framingham Heart Study, Framingham, Massachusetts, United States of America.
21
Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain.
22
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University New York, New York, United States of America; Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, New York, United States of America.
23
Université Lille 2, Lille, France; CNR-MAJ, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
24
University Paris Descartes, Sorbonne Paris V, Broca Hospital, Geriatrics department, Paris, France.
25
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America; Departments of Epidemiology and Global Health, University of Washington, Seattle, Washington, United States of America.
26
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, United States of America; Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America; Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
27
CNR-MAJ, Inserm U1079, Rouen University Hospital, 76031 France, Rouen, France.
28
Department of Medicine, University of Washington, Seattle, Washington, United States of America.
29
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, United States of America.
30
German Center for Neurodegenerative Diseases (DZNE), Bonn, and Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.
31
Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, United States of America.
32
Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom.
33
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
34
INSERM U1061, Faculty of Medicine, Hôpital La Colombière, Montpellier, France.
35
Departments of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
36
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Boston, Massachusetts, United States of America.
37
Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America.
38
King's College London, Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, Denmark Hill, London, United Kingom.
39
Inserm U897, Victor Segalen University, F-33076, Bordeaux, France.
40
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
41
Icelandic Heart Association, Kopavogur, Iceland.
42
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
43
Inserm U744, Lille, France; Institut Pasteur de Lille, Lille, France.
44
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
45
Discipline of Psychiatry, Trinity College, Dublin, Ireland.
46
Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
47
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
48
Aging Reasearch Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
49
Department of Medicine, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health, Seattle, Washington, United States of America.
50
Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
51
University of Bristol Institute of Clinical Neurosciences, School of Clinical Sciences, Frenchay Hospital, Bristol, United Kingdom.
52
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
53
Institute of Primary Care and Public Health, Cardiff University, Neuadd Meirionnydd, University Hospital of Wales, Heath Park, Cardiff, United Kingdom.
54
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada; Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
55
Neurology Department. IIB Sant Pau. Sant Pau Hospital. Universitat Autònoma de Barcelona, Barcelona, Spain; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain.
56
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, United States of America.
57
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America.
58
3rd Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
59
Clinical and Behavioral Neurology, Fondazione Santa Lucia, Roma, Italy.
60
MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
61
NEUROFARBA Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Centro di Ricerca, Trasferimento e Alta Formazione DENOTHE, University of Florence, Florence, Italy.
62
Department of Immunology, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain.
63
Dementia Research Center, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
64
Department of Molecular Neuroscience and Reta Lilla Weston Laboratories, Institute of Neurology, London, United Kingdom.
65
IRCCS Associazione Oasi Maria SS, Troina, Italy.
66
Oxford Healthy Aging Project (OHAP), Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom.
67
Cognitive Function and Ageing Study (CFAS), Institute of Public Health, University of Cambridge, Cambridge, United Kingdom.
68
University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
69
Neurological Clinic, University of Pisa, Pisa, Italy.
70
Urban Epidemiology, Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
71
Section of Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
72
Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
73
Department of Psychiatry and Psychotherapy, University of Bonn, Germany and German Center for Neurodegenerative Diseases (DZNE, Bonn), Bonn, Germany.
74
Department of Psychiatry, University of Frankfurt am Main, Frankfurt am Main, Germany (H.H.); Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany.
75
Gerontology and Geriatrics Research Laboratory, I.R.C.C.S. Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
76
Centro de Biología Molecular Severo Ochoa (CSIC-UAM); Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto de Investigación Sanitaria "Hospital la Paz" (IdIPaz), Madrid, Spain.
77
Department of Geriatrics,Center for Aging Brain,University of Bari, Bari, Italy.
78
Department of Neuroscience-University of Parma, Parma, Italy; Center for Cognitive Disorders AUSL, Parma, Italy.
79
Department Of Psychiatry, University Hospital, Saarland, Germany.
80
Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
81
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
82
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
83
National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, United States of America.
84
Genetica molecular-Huca-Oviedo, Oviedo, Spain.
85
Department of Psychiatry, University Hospital, Saarland, Germany.
86
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain.
87
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.
88
Neurology Service and CIBERNED, "Marqués de Valdecilla" University Hospital (University of Cantabria and IFIMAV), Santander, Spain.
89
Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, United States of America.
90
University of Iceland, Faculty of Medicine, Reykjavik, Iceland; Landspitali University Hospital, Reykjavik, Iceland.
91
Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
92
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
93
Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
94
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, United States of America; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, United States of America.
95
Laboratory of Epidemiology, Demography, and Biometry, National Institute of Health, Bethesda, Maryland, United States of America.
96
Aging Research Center, Department Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden; Department Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, Stockholm, Sweden.
97
Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, United Kingdom.
98
Departments of Neurology and Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
99
Department of Pathology, University of Washington, Seattle, Washington, United States of America.
100
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
101
INSERM UMR_S975-CNRS UMR 7225, Université Pierre et Marie Curie, Centre de recherche de l'Institut du Cerveau et de la Moëlle épinière-CRICM, Hôpital de la Salpêtrière, Paris France; AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
102
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
103
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, United States of America.
104
INSERM U1061, Faculty of Medicine, Hôpital La Colombière, Montpellier, France; Imperial College, London, United Kingdom.
105
Department of Biology, Brigham Young University, Provo, Utah, United States of America.
106
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America; Human Genetics Center and Div. of Epidemiology, University of Texas Health Sciences Center at Houston, Houston, Texas, United States of America.
107
Memory Clinic of Fundació ACE. Institut Català de Neurociències Aplicades, Barcelona, Spain; Hospital Universitari Vall d'Hebron - Institut de Recerca, Universitat Autònoma de Barcelona. (VHIR-UAB), Barcelona, Spain.
108
Department of Neurology, Medical University Graz, Graz, Austria.
109
Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany.
110
Inserm U897, Victor Segalen University, F-33076, Bordeaux, France; Centre de Mémoire de Ressources et de Recherche de Bordeaux, CHU de Bordeaux, Bordeaux, France.
111
Inserm U708, Victor Segalen University, Bordeaux, France.
112
Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, and German Center for Neurodegenerative Diseases (DZNE, Bonn), Bonn, Germany.
113
Department Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, Stockholm, Sweden; Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, KIADRC, Stockholm, Sweden.
114
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America.
115
Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
116
Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States of America; Fondation Jean Dausset- CEPH, Paris, France; McGill University and Génome Québec Innovation Centre, Montreal, Canada.
117
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, United States of America; Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States of America; Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States of America; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
118
Netherlands Consortium for Healthy Aging, Leiden, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Center for Medical Systems Biology, Leiden, The Netherlands.
119
Department of Psychiatry and Psychotherapy and Institute of Human Genetics, University of Bonn, Bonn, Germany.
120
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America; The Framingham Heart Study, Framingham, Massachusetts, United States of America.
121
Inserm U744, Lille, France; Université Lille 2, Lille, France; Institut Pasteur de Lille, Lille, France; CNR-MAJ, Centre Hospitalier Régional Universitaire de Lille, Lille, France; Centre Hospitalier Régional Universitaire de Lille, Lille, France.

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.

PMID:
24922517
PMCID:
PMC4055488
DOI:
10.1371/journal.pone.0094661
[Indexed for MEDLINE]
Free PMC Article

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