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Nat Genet. 2017 Sep;49(9):1373-1384. doi: 10.1038/ng.3916. Epub 2017 Jul 17.

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Sims R1, van der Lee SJ2, Naj AC3, Bellenguez C4,5,6, Badarinarayan N1, Jakobsdottir J7, Kunkle BW8, Boland A9, Raybould R1, Bis JC10, Martin ER8,11, Grenier-Boley B4,5,6, Heilmann-Heimbach S12,13, Chouraki V14,15, Kuzma AB16, Sleegers K17,18, Vronskaya M1, Ruiz A19, Graham RR20, Olaso R9, Hoffmann P12,13,21, Grove ML22, Vardarajan BN23,24,25, Hiltunen M26,27, Nöthen MM12,13, White CC28, Hamilton-Nelson KL8, Epelbaum J29, Maier W30,31, Choi SH14,32, Beecham GW8,11, Dulary C9, Herms S12,13,21, Smith AV7,33, Funk CC34, Derbois C9, Forstner AJ12,13, Ahmad S2, Li H34, Bacq D9, Harold D35, Satizabal CL14,15, Valladares O16, Squassina A36, Thomas R1, Brody JA10, Qu L16, Sánchez-Juan P37, Morgan T1, Wolters FJ2, Zhao Y16, Garcia FS38, Denning N1, Fornage M39, Malamon J16, Naranjo MCD38, Majounie E1, Mosley TH40, Dombroski B16, Wallon D41,42, Lupton MK43,44, Dupuis J32, Whitehead P8, Fratiglioni L45,46, Medway C47, Jian X39, Mukherjee S48, Keller L46, Brown K47, Lin H49, Cantwell LB16, Panza F50, McGuinness B51, Moreno-Grau S19, Burgess JD52, Solfrizzi V53, Proitsi P43, Adams HH2, Allen M52, Seripa D54, Pastor P55, Cupples LA15,32, Price ND34, Hannequin D42,56, Frank-García A57,58,59, Levy D14,15,60, Chakrabarty P61, Caffarra P62,63, Giegling I64, Beiser AS15,32, Giedraitis V65, Hampel H66,67,68, Garcia ME69, Wang X52, Lannfelt L65, Mecocci P55, Eiriksdottir G7, Crane PK48, Pasquier F70,71, Boccardi V55, Henández I19, Barber RC72, Scherer M73, Tarraga L19, Adams PM74, Leber M75, Chen Y32, Albert MS76, Riedel-Heller S77, Emilsson V7,78, Beekly D79, Braae A80, Schmidt R81, Blacker D82,83, Masullo C84, Schmidt H85, Doody RS86, Spalletta G87, Longstreth WT Jr88,89, Fairchild TJ90, Bossù P87, Lopez OL91,92, Frosch MP93, Sacchinelli E87, Ghetti B94, Yang Q32, Huebinger RM95, Jessen F30,31,75, Li S32, Kamboh MI96,97, Morris J98,99, Sotolongo-Grau O19, Katz MJ100, Corcoran C101, Dunstan M1, Braddel A1, Thomas C1, Meggy A1, Marshall R1, Gerrish A1, Chapman J1, Aguilar M102,103, Taylor S1, Hill M1, Fairén MD59,102, Hodges A104, Vellas B105, Soininen H27, Kloszewska I106, Daniilidou M107, Uphill J108, Patel Y43, Hughes JT43, Lord J47, Turton J47, Hartmann AM64, Cecchetti R55, Fenoglio C109, Serpente M109, Arcaro M109, Caltagirone C87, Orfei MD87, Ciaramella A87, Pichler S110, Mayhaus M110, Gu W110, Lleó A59,111, Fortea J59,111, Blesa R59,111, Barber IS80, Brookes K80, Cupidi C112, Maletta RG112, Carrell D113, Sorbi S114,115, Moebus S116, Urbano M54, Pilotto A54, Kornhuber J117, Bosco P118, Todd S51, Craig D51, Johnston J51, Gill M119, Lawlor B119, Lynch A119, Fox NC120, Hardy J120; 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Author information

1
Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
2
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
3
Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
4
INSERM, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.
5
Institut Pasteur de Lille, Lille, France.
6
University Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France.
7
Icelandic Heart Association, Kopavogur, Iceland.
8
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA.
9
CEA/Institut de Génomique, Centre National de Génotypage, Evry, France.
10
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
11
Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miami, Florida, USA.
12
Institute of Human Genetics, University of Bonn, Bonn, Germany.
13
Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
14
Boston University School of Medicine, Boston, Massachusetts, USA.
15
Framingham Heart Study, Framingham, Massachusetts, USA.
16
Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
17
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
18
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
19
Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
20
Immunology Biomarkers Group, Genentech, South San Francisco, California, USA.
21
Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
22
School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
23
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, USA.
24
Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA.
25
Department of Neurology, Columbia University, New York, New York, USA.
26
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
27
Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
28
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
29
UMR 894, Center for Psychiatry and Neuroscience, INSERM, Université Paris Descartes, Paris, France.
30
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
31
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
32
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
33
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
34
Institute for Systems Biology, Seattle, Washington, USA.
35
School of Biotechnology, Dublin City University, Dublin, Ireland.
36
Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
37
Neurology Service and CIBERNED, 'Marqués de Valdecilla' University Hospital (University of Cantabria and IFIMAV), Santander, Spain.
38
Department of Immunology, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain.
39
Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
40
Departments of Medicine, Geriatrics, Gerontology and Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
41
Centre Hospitalier du Rouvray, Sotteville les Rouen, France.
42
INSERM U1079, Rouen University, IRIB, Normandy University, Rouen, France.
43
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
44
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
45
Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
46
Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
47
Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
48
Department of Medicine, University of Washington, Seattle, Washington, USA.
49
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
50
Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
51
Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK.
52
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
53
Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari Aldo Moro, Bari, Italy.
54
Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
55
Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.
56
Department of Neurology, Rouen University Hospital, Rouen, France.
57
Department of Neurology, University Hospital La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
58
Instituto de Investigación Sanitaria Hospital la Paz (IdiPAZ), Madrid, Spain.
59
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
60
National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
61
Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
62
Department of Neuroscience, University of Parma, Parma, Italy.
63
Center for Cognitive Disorders AUSL, Parma, Italy.
64
Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany.
65
Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
66
AXA Research Fund and UPMC Chair, Paris, France.
67
Sorbonne Universités, Université Pierre et Marie Curie, Paris, France.
68
Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A) and Institut du Cerveau et de la Moelle Épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
69
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.
70
Centre Hospitalier Universitaire de Lille, Epidemiology and Public Health Department, Lille, France.
71
INSERM UMRS 1171, CNR-Maj, Lille, France.
72
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA.
73
Department of Primary Medical Care, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
74
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
75
Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
76
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
77
Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
78
Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland.
79
National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA.
80
Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, UK.
81
Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria.
82
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
83
Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.
84
Department of Neurology, Catholic University of Rome, Rome, Italy.
85
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
86
Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas, USA.
87
Experimental Neuropsychiatry Laboratory, IRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Rome, Italy.
88
Department of Neurology, University of Washington, Seattle, Washington, USA.
89
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
90
Office of Strategy and Measurement, University of North Texas Health Science Center, Fort Worth, Texas, USA.
91
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
92
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
93
C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
94
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, USA.
95
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
96
Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
97
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
98
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
99
Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, USA.
100
Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.
101
Department of Mathematics and Statistics, Utah State University, Logan, Utah, USA.
102
Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain.
103
Memory Unit, Department of Neurology, Hospital Universitario Mútua Terrassa, Terrassa, Barcelona, Spain.
104
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
105
INSERM U558, University of Toulouse, Toulouse, France.
106
Elderly and Psychiatric Disorders Department, Medical University of Lodz, Lodz, Poland.
107
Department of Health Sciences, Psychiatry for the Elderly, University of Leicester, Leicester, UK.
108
Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
109
Department of Pathophysiology and Transplantation, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
110
Department of Psychiatry and Psychotherapy, University Hospital, Saarland, Germany.
111
Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
112
Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
113
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
114
NEUROFARBA (Department of Neuroscience, Psychology, Drug Research and Child Health), University of Florence, Florence, Italy.
115
IRCCS 'Don Carlo Gnocchi', Florence, Italy.
116
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
117
Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany.
118
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Associazione Oasi Maria Santissima Srl, Troina, Italy.
119
Mercers Institute for Research on Aging, St. James Hospital and Trinity College, Dublin, Ireland.
120
Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK.
121
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
122
Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, USA.
123
Michigan Alzheimer Disease Center, Ann Arbor, Michigan, USA.
124
Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
125
Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA.
126
Department of Neurology, Indiana University, Indianapolis, Indiana, USA.
127
Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, USA.
128
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
129
Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, Wisconsin, USA.
130
Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
131
Wisconsin Alzheimer's Disease Research Center, Madison, Wisconsin, USA.
132
Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, USA.
133
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
134
Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA.
135
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
136
Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, USA.
137
Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
138
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
139
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
140
VA Puget Sound Health Care System/GRECC, Seattle, Washington, USA.
141
Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
142
Swedish Medical Center, Seattle, Washington, USA.
143
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
144
Department of Medicine, Duke University, Durham, North Carolina, USA.
145
University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
146
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.
147
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
148
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
149
Department of Pathology and Immunology, Washington University, St. Louis, Missouri, USA.
150
USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA.
151
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
152
Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, USA.
153
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
154
Department of Neurology, University of Southern California, Los Angeles, California, USA.
155
Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.
156
Department of Neurology, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, USA.
157
Department of Neurology, University of California, Irvine, Irvine, California, USA.
158
Department of Neurology, University of California, Davis, Sacramento, California, USA.
159
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California, USA.
160
Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, USA.
161
Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
162
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
163
Sanders-Brown Center on Aging, Department of Biostatistics, University of Kentucky, Lexington, Kentucky, USA.
164
Department of Psychiatry, New York University, New York, New York, USA.
165
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
166
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
167
Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, USA.
168
Neurogenetics Program, University of California, Los Angeles, Los Angeles, California, USA.
169
Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
170
Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
171
Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.
172
Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
173
Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
174
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA.
175
Department of Pathology, Duke University, Durham, North Carolina, USA.
176
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
177
Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, USA.
178
Sanders-Brown Center on Aging, College of Public Health, Department of Epidemiology, University of Kentucky, Lexington, Kentucky, USA.
179
Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California, USA.
180
Department of Biostatistics, Boston University, Boston, Massachusetts, USA.
181
Department of Ophthalmology, Boston University, Boston, Massachusetts, USA.
182
Department of Neurology, Oregon Health &Science University, Portland, Oregon, USA.
183
Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, USA.
184
Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, California, USA.
185
Department of Neurology, Boston University, Boston, Massachusetts, USA.
186
Department of Pathology, Boston University, Boston, Massachusetts, USA.
187
Department of Neuropsychology, University of California, San Francisco, San Francisco, California, USA.
188
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, USA.
189
Department of Neurology, Emory University, Atlanta, Georgia, USA.
190
Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, USA.
191
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
192
Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA.
193
Department of Medicine-Pulmonary, New York University, New York, New York, USA.
194
Department of Neurology, University of Miami, Miami, Florida, USA.
195
Department of Pathology, University of California, San Diego, La Jolla, California, USA.
196
School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, Washington, USA.
197
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
198
Department of Pathology, University of Southern California, Los Angeles, California, USA.
199
Department of Neurology, Washington University, St. Louis, Missouri, USA.
200
Internal Medicine, Division of Geriatrics, University of North Texas Health Science Center, Fort Worth, Texas, USA.
201
Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
202
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
203
Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
204
Alzheimer's Disease Center, New York University, New York, New York, USA.
205
Department of Epidemiology, Columbia University, New York, New York, USA.
206
Department of Neurology, University of California, Los Angeles, Los Angeles, California, USA.
207
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
208
Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
209
Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, USA.
210
Department of Psychiatry, University of Southern California, Los Angeles, California, USA.
211
Department of Pathology, University of Washington, Seattle, Washington, USA.
212
Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
213
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
214
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
215
Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA.
216
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.
217
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York, USA.
218
Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
219
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA.
220
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
221
Department of Pathology, Oregon Health &Science University, Portland, Oregon, USA.
222
Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
223
Department of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium.
224
Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven, Leuven, Belgium.
225
Department of Geriatric Medicine, Genetics Unit, Karolinska University Hospital Huddinge, Stockholm, Sweden.
226
Department of Neurobiology, Care Sciences and Society, KIADRC, Karolinska Institutet, Stockholm, Sweden.
227
Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.
228
CHU Lille, Memory Center of Lille (Centre Mémoire de Ressources et de Recherche), Lille, France.
229
University Paris Descartes, EA 4468, AP-HP, Hôpital Broca, Geriatrics Department, Paris, France.
230
University of Bordeaux, Neuroepidemiology, Bordeaux, France.
231
INSERM, Neuroepidemiology, UMR 897, Bordeaux, France.
232
INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Institut du Cerveau et de la Moelle Épinière, Paris, France.
233
AP-HP, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France.
234
INSERM U1061, La Colombière Hospital, Montpellier, France.
235
Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
236
Institut des Neurosciences Translationnelles de Paris (IHU-A-ICM), Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.
237
INSERM, CNRS, UMRS 975, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.
238
Sorbonne Universités, Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
239
Department of Family Medicine, University of Washington, Seattle, Washington, USA.
240
Centre for Public Health, University of Iceland, Reykjavik, Iceland.
241
Group Health Research Institute, Group Health, Seattle, Washington, USA.
242
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
243
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
244
Molecular Genetics Laboratory-Hospital, University of Central Asturias, Oviedo, Spain.
245
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
246
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
247
Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands.
248
Arizona Alzheimer's Consortium, Phoenix, Arizona, USA.
249
Banner Alzheimer's Institute, Phoenix, Arizona, USA.
250
Department of Psychiatry, University of Arizona, Phoenix, Arizona, USA.
251
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
252
Departments of Psychiatry, Medicine, and Family and Community Medicine and South Texas Veterans Health Administration Geriatric Research Education and Clinical Center (GRECC), University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
253
Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.
254
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
255
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
256
Department of Experimental and Clinical Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
257
PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
258
Institute of Neurology, Catholic University of Sacred Hearth, Rome, Italy.
259
Departments of Neurology, Pharmacology, and Neuroscience, Texas Tech University Health Science Center, Lubbock, Texas, USA.
260
Department of Psychiatry, Charité University Medicine, Berlin, Germany.
261
Institute of Public Health, University of Cambridge, Cambridge, UK.
262
Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal.
263
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
264
Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neuroscience Research Group, University of Manchester, Manchester, UK.
265
3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
266
Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.
267
Department of Psychiatry, University of Oxford, Oxford, UK.
268
Florida Alzheimer's Disease Research Center, Gainesville, Florida, USA.
269
Center for Translational and Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, USA.
270
Department of Health Services, University of Washington, Seattle, Washington, USA.
271
Memory Research and Resources Center, CMRR of Montpellier, Department of Neurology, Hospital Gui de Chauliac, Montpellier, France.
272
Department of Neurology, Montpellier University, Montpellier, France.
273
Memory Research and Resources Center, CMRR de Bordeaux, Bordeaux, France.
274
Neurogenetics Laboratory, Division of Neurosciences, Centre for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain.
275
Department of Neurology, Complejo Asistencial Universitario de Palencia, Palencia, Spain.
276
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
277
Departments of Biology and Neuroscience, Brigham Young University, Provo, Utah, USA.
278
Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
279
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
280
University of Bordeaux, Neuroepidemiology, UMR 897, Bordeaux, France.

Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

PMID:
28714976
PMCID:
PMC5669039
DOI:
10.1038/ng.3916
[Indexed for MEDLINE]
Free PMC Article

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