Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Nature Genetics Année : 2017

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

Rebecca Sims (1) , Sven van Der Lee (2) , Adam Naj (3) , Céline Bellenguez (4) , Nandini Badarinarayan (1) , Johanna Jakobsdottir (5) , Brian Kunkle (6) , Anne Boland (7) , Rachel Raybould (1) , Joshua Bis (8) , Eden Martin (6, 9) , Benjamin Grenier-Boley (10) , Stefanie Heilmann-Heimbach (11) , Vincent Chouraki (10) , Amanda Kuzma (3) , Kristel Sleegers (12) , Maria Vronskaya (1) , Agustin Ruiz (13) , Robert Graham (14) , Robert E Olaso (15) , Per Hoffmann (16) , Megan Grove (17) , Badri Vardarajan (18) , Mikko Hiltunen (19) , Markus M. Nöthen (20) , Charles White (21) , Kara Hamilton-Nelson (22) , Jacques Epelbaum (23) , Wolfgang Maier (24) , Seung-Hoan Choi (25) , Gary Beecham (22) , Cécile Dulary (15) , Stefan Herms (26) , Albert Smith (5) , Cory Funk (27) , Céline Derbois (15) , Andreas Forstner (28) , Shahzad Ahmad (2) , Hongdong Li (29) , Delphine Bacq (15) , Denise Harold (30) , Claudia Satizabal (31) , Otto Valladares (32) , Alessio Squassina (33) , Rhodri Thomas (1) , Jennifer Brody (34) , Liming Qu (3) , Pascual Sanchez-Juan (35) , Taniesha Morgan (1) , Frank Wolters (2) , Yi Zhao (3) , Florentino Sanchez Garcia (36) , Nicola Denning (1) , Myriam Fornage (17) , John Malamon (3) , Maria Candida Deniz Naranjo (36) , Elisa Majounie (37) , Thomas Mosley (38) , Beth A. Dombroski (39) , David Wallon (40, 41) , Michelle Lupton (42) , Josée Dupuis (31) , Patrice Whitehead (43) , Laura Fratiglioni (44) , Christopher Medway (45) , Xueqiu Jian (46) , Shubhabrata Mukherjee (34) , Lina Keller (47) , Kristelle Brown (45) , Honghuang Lin (31) , Laura Cantwell (3) , Francesco Panza (48) , Bernadette Mcguinness (49) , Sonia Moreno-Grau (13) , Jeremy Burgess (50) , Vincenzo Solfrizzi (48) , Petra Proitsi (51) , Hieab Adams (2) , Mariet Allen (50) , Davide Seripa (52) , Pau Pastor (53) , L Adrienne Cupples (54) , Nathan Price (27) , Didier Hannequin (55, 41) , Ana Frank-García (56, 57) , Daniel Lévy (58, 54) , Paramita Chakrabarty (59) , Paolo Caffarra (60, 61) , Ina Giegling (26) , Alexa Beiser (62) , Vilmantas Giedraitis (63) , Harald Hampel (64) , Melissa E. Garcia (65) , Xue Wang (66) , Lars Lannfelt (67) , Patrizia Mecocci (68) , Gudny Eiriksdottir (5) , Paul Crane (34) , Florence Pasquier (69) , Virginia Boccardi (70) , Isabel Henández (13) , Robert Barber (71) , Martin Scherer (72) , Lluis Tarraga (13) , Perrie Adams (73) , Markus Leber (74) , Yuning Chen (75) , Marilyn Albert (76) , Steffi Riedel-Heller (77) , Valur Emilsson (78) , Duane Beekly (34) , Anne Braae (45) , Reinhold Schmidt (79) , Deborah Blacker (80) , Carlo Masullo (81) , Helena Schmidt (82) , Rachelle Doody (83) , Gianfranco Spalletta (83) , W T Longstreth Jr (34) , Thomas Fairchild (84) , Paola Bossù (85) , Oscar López (86) , Matthew P Frosch (87) , Eleonora Sacchinelli (85) , Bernardino Ghetti (88) , Qiong Yang (89) , Ryan Huebinger (73) , Frank Jessen (79) , Shuo Li (90) , M Ilyas Kamboh (91) , Oscar Sotolongo-Grau (13) , Mindy Katz (92) , Chris Corcoran (93) , Melanie Dunstan (1) , Amy Braddel (1) , Charlene Thomas (1) , Alun Meggy (1) , Rachel Marshall (1) , Amy Gerrish (1) , Jade Chapman (1) , Miquel Aguilar (94, 95) , Sarah Taylor (1) , Matt Hill (1) , Mònica Díez Fairén (94, 57) , Angela Hodges (96) , Bruno Vellas (97) , Hilkka Soininen (19) , Iwona Kloszewska (98) , Makrina Daniilidou (99) , James Uphill (100) , Yogen Patel (96) , Joseph Hughes (96) , Jenny Lord (45) , James Turton (45) , Annette M. Hartmann (26) , Roberta Cecchetti (53) , Chiara Fenoglio (101) , Maria Serpente (102) , Marina Arcaro (102) , Carlo Caltagirone (103) , Maria Donata Orfei (85) , Antonio Ciaramella (85) , Sabrina Pichler (104) , Manuel Mayhaus (104) , Wei Gu , Alberto Lleó (57, 105) , Juan Fortea (57, 105) , Rafael Blesa (57, 105) , Imelda Barber (45) , Keeley Brookes (45) , Chiara Cupidi (106) , Raffaele Giovanni Maletta (106) , David Carrell (34) , Sandro Sorbi (107) , Susanne Moebus (108) , Maria Joana Urbano (109) , Alberto Pilotto (52) , Johannes Kornhuber (110) , Paolo Bosco (111) , Stephen Todd (112) , David Craig (113) , Janet Johnston (42) , Michael Gill (114) , Brian Lawlor (115) , Aoibhinn Lynch (42) , Nick Fox (116) , John Hardy (117) , Roger Albin (118) , Liana G Apostolova (119) , Steven Arnold (3) , Sanjay Asthana (120) , Craig Atwood (120) , Clinton Baldwin (25) , Lisa L Barnes (121) , Sandra Barral (122) , Thomas Beach (123) , James Becker (124) , Eileen Bigio (125) , Thomas Bird (34) , Bradley Boeve (126) , James Bowen (127) , Adam Boxer (128) , James Burke (129) , Jeffrey Burns (130) , Joseph D. Buxbaum (131) , Nigel Cairns (132) , Chuanhai Cao (133) , Chris Carlson (134) , Cynthia Carlsson (120) , Regina Carney (43) , Minerva Carrasquillo (50) , Steven Carroll (135) , Carolina Ceballos Diaz (59) , Helena Chui (136) , David Clark (137) , David Cribbs (138) , Elizabeth Crocco (43) , Charles Decarli (139) , Malcolm Dick (140) , Ranjan Duara (141) , Denis Evans (142) , Kelley Faber (143) , Kenneth Fallon (144) , David Fardo (145) , Martin Farlow (143) , Steven Ferris (146) , Tatiana Foroud (147) , Douglas Galasko (148) , Marla Gearing (149) , Daniel H. Geschwind (150) , John Gilbert (43) , Neill Graff-Radford (50) , Robert Green (151) , John Growdon (152) , Ronald Hamilton (91) , Lindy Harrell (144) , Lawrence Honig (18) , Matthew Huentelman (153) , Christine Hulette (129) , Bradley T. Hyman (154) , Gail Jarvik (34) , Erin Abner (145) , Lee-Way Jin (155) , Gyungah Jun (25) , Anna Karydas (128) , Jeffrey Kaye (156) , Ronald Kim (140) , Neil Kowall (25) , Joel Kramer (128) , Frank Laferla (140) , James Lah (149) , James Leverenz (157) , Allan Levey (158) , Ge Li (159) , Andrew Lieberman (118) , Kathryn Lunetta (25) , Constantine Lyketsos (160) , Daniel Marson (144) , Frank Martiniuk (146) , Deborah Mash (161) , Eliezer Masliah (162) , Wayne Mccormick (34) , Susan Mccurry (34) , Andrew Mcdavid (134) , Ann C Mckee (31) , Marsel Mesulam (125) , Bruce Miller (163) , Carol Miller (136) , Joshua Miller (164) , John Morris (132) , Jill Murrell (165) , Amanda Myers (43) , Sid O'Bryant (166) , John Olichney (164) , Vernon Pankratz (167) , Joseph Parisi (126) , Henry Paulson (118) , William Perry (43) , Elaine Peskind (34) , Aimee Pierce (140) , Wayne Poon (168) , Huntington Potter (169) , Joseph Quinn (170) , Ashok Raj (133) , Murray Raskind (34) , Barry Reisberg (146) , Christiane Reitz (18) , John Ringman (171) , Erik Roberson (144) , Ekaterina Rogaeva (172) , Howard Rosen (128) , Roger Rosenberg (73) , Mark Sager (120) , Andrew Saykin (173) , Julie A Schneider (121) , Lon S Schneider (174) , William Seeley (128) , Amanda Smith (133) , Joshua Sonnen (34) , Salvatore Spina (175) , Robert Stern (31) , Russell Swerdlow (130) , Rudolph E. Tanzi (176) , Tricia Thornton-Wells (177) , John Q Trojanowski (178) , Juan Troncoso (79) , Vivianna van Deerlin (178) , Linda van Eldik (145) , Harry V. Vinters (179) , Jean Paul Vonsattel (18) , Sandra Weintraub (125) , Kathleen Welsh-Bohmer (129) , Kirk Wilhelmsen (180) , Jennifer Williamson (18) , Thomas Wingo (149) , Randall Woltjer (156) , Clinton Wright (43) , Chang-En Yu (181) , Lei Yu (121) , Fabienne Garzia (182) , Feroze Golamaully (182) , Gislain Septier (182) , Sebastien Engelborghs (183) , Rik Vandenberghe (12) , Peter de Deyn (184) , Carmen Muñoz Fernadez (36) , Yoland Aladro Benito (36) , Hakan Thonberg (185) , Charlotte Forsell (186, 185) , Lena Lilius (186, 185) , Anne Kinhult-Stählbom (186, 185) , Lena Kilander (63) , Rosemarie Brundin (63) , Letizia Concari (60, 61) , Seppo Helisalmi (187, 19) , Anne Maria Koivisto (187, 19) , Annakaisa Haapasalo (187, 19) , Vincent Dermecourt (188) , Nathalie Fievet (189) , Olivier Hanon (190) , Carole Dufouil (191) , Alexis Brice (192) , Karen Ritchie (193) , Bruno Dubois (194) , Jayanadra Himali (31) , C Dirk Keene (34) , Joann Tschanz (93) , Annette Fitzpatrick (195) , Walter Kukull (34) , Maria Norton (93) , Thor Aspelund (78) , Eric Larson (34) , Ron Munger (93) , Jerome Rotter (196) , Richard Lipton (197) , María Bullido (198, 57, 199) , Albert Hofman (200) , Thomas Montine (34) , Eliecer Coto (201) , Eric Boerwinkle (202) , Ronald Petersen (126) , Victoria Alvarez (201) , Fernando Rivadeneira (203) , Eric Reiman (204, 205, 206) , Maura Gallo (106) , Christopher O'Donnell (54) , Joan Reisch (73) , Amalia Cecilia Bruni (106) , Donald Royall (207) , Martin Dichgans (79) , Mary Sano (208) , Daniela Galimberti (209) , Peter St George-Hyslop (210) , Elio Scarpini (209) , Debby Tsuang (34, 211) , Michelangelo Mancuso (212) , Ubaldo Bonuccelli (212) , Ashley Winslow (213) , Antonio Daniele (214) , Chuang-Kuo Wu (215) , Oliver Peters (173) , Benedetta Nacmias (107) , Matthias Riemenschneider (216) , Reinhard Heun (217) , Carol Brayne (218) , David C. Rubinsztein (219) , Jose Bras (220) , Rita Guerreiro (220) , Ammar Al-Chalabi (221) , Christopher Shaw (222) , John Collinge (100) , David Mann (223) , Magda Tsolaki (224) , Jordi Clarimón (57, 225) , Rebecca Sussams (226) , Simon Lovestone (227) , Michael O'Donovan (1) , Michael Owen (228) , Timothy Behrens (229) , Simon Mead (230) , Alison Goate (231) , André G. Uitterlinden (232) , Clive Holmes (211) , Carlos Cruchaga (233) , Martin Ingelsson (63) , David A Bennett (121) , John Powell (96) , Todd Golde (59) , Caroline Graff (185) , Philip L de Jager (234) , Kevin Morgan (235) , Nilufer Ertekin-Taner (236) , Onofre Combarros (57) , Bruce Psaty (34, 57) , Peter Passmore (113) , Steven Younkin (50) , Claudine Berr (193) , Vilmundur Gudnason (237) , Dan Rujescu (238) , Dennis Dickson (50) , Jean-François Dartigues (239) , Anita Destefano (25) , Sara Ortega-Cubero (57) , Hakon Hakonarson (240) , Dominique Campion (40) , Merce Boada (241) , John Keoni Kauwe (13) , Lindsay Farrer (31) , Christine van Broeckhoven (242) , M Arfan Ikram (2) , Lesley Jones (243) , Jonathan Haines (244) , Christophe Tzourio (245) , Lenore Launer (65) , Valentina Escott-Price (246) , Richard P. Mayeux (247) , Jean-François Deleuze (15) , Najaf Amin (248) , Peter Holmans (246) , Margaret Pericak-Vance (6) , Philippe Amouyel (4) , Cornelia M. van Duijn (200) , Alfredo Ramírez (249) , Li-San Wang (250) , Jean-Charles Lambert (4) , Sudha Seshadri (31, 251) , Julie Williams (228) , Gerard D. Schellenberg (39)
1 Institute of Psychological Medicine and Clinical Neurosciences
2 Erasmus MC - Erasmus University Medical Center [Rotterdam]
3 HUP - Hospital of the University of Pennsylvania
4 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
5 IHA - Icelandic Heart Association [Kopavogur, Iceland]
6 John P. Hussman Institute for Human Genomics [Miami, FL, USA]
7 JACOB - Institut de Biologie François JACOB
8 Department of Medicine
9 Department of Human Genetics - Dr. John T. Macdonald Foundation [Miami, FL, USA]
10 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
11 Institute of Human Genetics - Department of Genomics [Bonn, Germany]
12 Department of Molecular Genetics
13 Institut Català de Neurociències Aplicades [Barcelona, Spain]
14 Well Advanced Solutions
15 CNG - Centre National de Génotypage
16 Translational Centre for Regenerative Medicine (TRM); Department of Cell Therapy
17 UTHealth - The University of Texas Health Science Center at Houston
18 Columbia University [New York]
19 University of Eastern Finland
20 Life & Brain Center - Department of Genomics
21 GReD - Génétique, Reproduction et Développement
22 John P. Hussman Institute for Human Genomics
23 Neurobiologie de la Croissance et de la Senescence
24 SFB 833 - Emmy Noether Project
25 BU - Boston University [Boston]
26 Department of Genomics
27 Institute for Systems Biology [Seattle, WA, USA]
28 UKB - Universitätsklinikum Bonn
29 Centre of Excellence for Robotic Vision [Canberra]
30 School of Medicine - Neuroscience and Mental Health Research Institute [Cardiff, UK]
31 BUSM - Boston University School of Medicine
32 Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
33 Section of Neuroscience and Clinical Pharmacology
34 University of Washington [Seattle]
35 Department of Epidemiology and Biostatistics
36 Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain]
37 Department of Neurodegenerative Diseases
38 UMMC - University of Mississippi Medical Center
39 Penn Neurodegeneration Genomics Center - Pathology and Laboratory Medicine [Philadelphia, PA, USA]
40 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
41 GMFC - Génétique du cancer et des maladies neuropsychiatriques
42 Bioinformatics
43 University of Miami [Coral Gables]
44 ARC - Aging Research Center [Karolinska Institutet]
45 UON - University of Nottingham, UK
46 University of Texas Health Science Center
47 Department of Neurobiology, Caring Sciences and Society (NVS)
48 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
49 Ageing Group, Centre for Public Health
50 Mayo Clinic [Jacksonville]
51 Maurice Wohl Clinical Neuroscience Institut
52 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo]
53 UNIPG - Università degli Studi di Perugia = University of Perugia
54 Framingham Heart Study
55 CHU Rouen
56 UAM - Universidad Autónoma de Madrid
57 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
58 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
59 UF - University of Florida [Gainesville]
60 UNIPR - Università degli studi di Parma = University of Parma
61 Center for Cognitive Disorders AUSL [Parma, Italy]
62 School of Public Health [Boston]
63 Uppsala University
64 IM2A - Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre]
65 NIA - National Institute on Aging [Bethesda, USA]
66 Xjtu - Xi'an Jiaotong University
67 Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
68 Institute of Gerontology and Geriatrics
69 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
70 Geriatric Medicine and Metabolic Diseases
71 Departments of Nuclear Medicine
72 University Medical Centre Hamburg-Eppendorf [Hamburg, Germany]
73 University of Texas Southwestern Medical Center [Dallas]
74 University of Cologne
75 LERIA - Laboratoire d'Etudes et de Recherche en Informatique d'Angers
76 JHU - Johns Hopkins University
77 Leipzig University / Universität Leipzig
78 University of Iceland [Reykjavik]
79 Metacohorts Consortium
80 Harvard School of Public Health
81 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
82 Medical University Graz
83 BCM - Baylor College of Medicine
84 University of North Texas Health Science Center [Fort Worth]
85 IRCCS - Santa Lucia Foundation
86 Nextel S.A. [Bilbao]
87 Massachusetts General Hospital [Boston]
88 Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center
89 JISAO - Joint Institute for the Study of the Atmosphere and Ocean
90 Beijing University of Technology
91 PITT - University of Pittsburgh
92 Saul B. Korey Department of Neurology
93 USU - Utah State University
94 Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain]
95 Hospital Universitario Mutua de Terrassa
96 King‘s College London
97 Département de neurologie [Montpellier]
98 MUL - Medical University of Łódź
99 University of Leicester
100 Department of Neurodegenerative Diseases
101 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
102 UNIMI - Università degli Studi di Milano = University of Milan
103 Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome]
104 UKS - Saarland University Hospital
105 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
106 CRN - ASP Catanzaro - Regional Neurogenetic Centre [Lamezia Terme, Italy]
107 UniFI - Università degli Studi di Firenze = University of Florence
108 Institute for Medical Informatics, Biometry and Epidemiology
109 Universidade do Porto = University of Porto
110 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
111 Experimental and Clinical Pharmacology
112 Ageing Group, Centre for Public Health
113 QUB - Queen's University [Belfast]
114 St. James Hospital and Trinity College [Dublin, Ireland]
115 School of Medicine [Dublin]
116 University of Sheffield [Sheffield]
117 Lancaster University
118 University of Michigan [Ann Arbor]
119 David Geffen School of Medicine [Los Angeles]
120 University of Wisconsin-Madison
121 Rush Alzheimer Disease Center [Chicago, IL, États-Unis]
122 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
123 School of Engineering [Cardiff]
124 Department of Psychiatry [Pittsburgh]
125 Northwestern University Feinberg School of Medicine
126 Mayo Clinic [Rochester]
127 Swedish Medical Center [Seattle, WA, USA]
128 UC San Francisco - University of California [San Francisco]
129 Duke University [Durham]
130 University of Kansas Medical Center [Kansas City, KS, USA]
131 Laboratory of Molecular Neuropsychiatry
132 WUSTL - Washington University in Saint Louis
133 USF - University of South Florida [Tampa]
134 FHCRC - Fred Hutchinson Cancer Research Center [Seattle]
135 MUSC - Medical University of South Carolina [Charleston]
136 USC - University of Southern California
137 LANL - Los Alamos National Laboratory
138 CBD - Centre de biologie du développement
139 UCDavis-Neuro - Neurology Department, University of California, Davis
140 UC Irvine - University of California [Irvine]
141 Mount Sinai Medical Center
142 Rush University Medical Center [Chicago]
143 Indiana State University
144 UAB - University of Alabama at Birmingham [ Birmingham]
145 UK - University of Kentucky
146 NYU - New York University [New York]
147 Department of Medical and Molecular Genetics
148 Department of Epidemiology and biostatistics
149 Emory University [Atlanta, GA]
150 Department of Neurology
151 BWH - Brigham & Women’s Hospital [Boston]
152 HMS - Harvard Medical School [Boston]
153 Department of Medical Genetics
154 Alzheimer Disease Research Laboratory
155 UC Davis - University of California [Davis]
156 OHSU - Oregon Health and Science University [Portland]
157 Cleveland Clinic
158 Department of Neurology
159 LISTIC - Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance
160 Department of Psychiatry
161 Douglas Mental Health University Institute [Montréal]
162 Department of neurosciences
163 Department of Physics and Astronomy [Fort Worth]
164 CS - UC Davis - Department of Computer Science [Univ California Davis]
165 Indiana University School of Medicine
166 IAADR - Institute for Aging and Alzheimer’s Disease Research [Fort Worth]
167 Department of Laboratory Medicine and Pathology
168 Institute for Memory Impairments and Neurological Disorders [Irvine]
169 University of Colorado Anschutz [Aurora]
170 Department of Neurology
171 UCLA - University of California [Los Angeles]
172 Tanz Center Research in Neurodegenerative Diseases [Toronto]
173 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
174 Keck School of Medicine [Los Angeles]
175 Indiana University [South Bend]
176 Massachusetts General Hospital
177 Novartis Institutes for Biomedical Research [Cambridge, MA, USA]
178 Perelman School of Medicine
179 Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology
180 UNC - University of North Carolina [Chapel Hill]
181 Department of Medicine
182 IG - Institut de Génomique d'Evry
183 UA - University of Antwerp
184 Institute Born-Bunge
185 Karolinska Institutet [Stockholm]
186 Karolinska University Hospital [Stockholm]
187 University of Kuopio
188 CMRR - Centre Mémoire de Ressources et de Recherche [Lille-Bailleul]
189 Laboratoire d'Analyse Génomique
190 Dpt Gériatrie [CHU Broca]
191 Neuroépidémiologie
192 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
193 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
194 GRC 21 - APM - Groupe de recherche clinique Alzheimer Precision Medicine
195 Department of Epidemiology, University of Washington
196 School of Medicine [Los Angeles]
197 Albert Einstein College of Medicine [New York]
198 IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain]
199 IFT - Instituto de Física Teórica UAM/CSIC
200 Department of Internal Medicine
201 University of Central Asturias [Oviedo, Spain]
202 Human Genome Sequencing Center, Baylor College of Medicine
203 Department of Epidemiology
204 Translational Genomics Research Institute [Phoenix, AZ, USA]
205 University of Arizona
206 Banner Alzheimer's Institute [Phoenix, AZ, États-Unis]
207 University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA]
208 Mount Sinai School of Medicine
209 Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico
210 Centre for Research in Neurodegenerative Diseases
211 VA Puget Sound Health Care System/GRECC [Seattle, WA, USA]
212 University of Pisa - Università di Pisa
213 Pfizer Worldwide Research and Development [Cambridge, MA, USA]
214 Unicatt - Università cattolica del Sacro Cuore [Piacenza e Cremona]
215 Texas Tech University Health Sciences Center
216 Saarland University [Saarbrücken]
217 Universität Bonn = University of Bonn
218 Department of Public Health and Primary Care
219 CIMR - Cambridge Institute for Medical Research
220 Department of Molecular Neurosciences
221 Institute of Psychiatry
222 UBC - University of British Columbia
223 the Clinical Neuroscience Research Group
224 Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa
225 University of Barcelona
226 University of Southampton
227 POWIC - Department of Psychiatry [Oxford]
228 School of Psychology [Cardiff University]
229 Department of Medical Sciences
230 UCL Queen Square Institute of Neurology
231 Department of Psychiatry
232 Netherlands Genomics Initiative
233 School of Medecine
234 CTCN - Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis]
235 School of Life Sciences
236 Department of Neuroscience
237 Icelandic Heart Association
238 Klinik für Psychiatrie
239 Epidémiologie et Biostatistique [Bordeaux]
240 The Center for Applied Genomics
241 Clínica Universidad de Navarra [Pamplona]
242 Neurodegenerative Brain Diseases Group
243 MRC Centre for Neuropsychiatric Genetics and Genomics
244 BYU - Brigham Young University
245 ISPED - Institut de Santé Publique, d'Epidémiologie et de Développement
246 Cardiff University
247 The Gertrude H Sergivesky Center
248 Genetic Epidemiology Unit
249 Section of Clinical and Molecular Neurogenetics
250 University of Pennsylvania - Department of Pathology & Laboratory Medecine
251 Framingham Heart Study [Framingham, MA, USA]
Anne Boland
Stefan Herms
Andreas Forstner
Michelle Lupton
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Xue Wang
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Gianfranco Spalletta
Paola Bossù
Mindy Katz
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Bruno Vellas
Hilkka Soininen
Joseph Hughes
Wei Gu
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Stephen Todd
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David Craig
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Janet Johnston
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Aoibhinn Lynch
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Nick Fox
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John Hardy
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Thomas Beach
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David Cribbs
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James Leverenz
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Constantine Lyketsos
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John Morris
Peter de Deyn
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Lena Kilander
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Carole Dufouil
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Eric Larson
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Ron Munger
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Carol Brayne
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Ammar Al-Chalabi
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Michael Owen
Alison Goate
Caroline Graff
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Peter Passmore
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Hakon Hakonarson
Dominique Campion
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Jean-François Deleuze
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Peter Holmans
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Résumé

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.
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Dates et versions

inserm-02466466 , version 1 (04-02-2020)

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Rebecca Sims, Sven van Der Lee, Adam Naj, Céline Bellenguez, Nandini Badarinarayan, et al.. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics, 2017, 49 (9), pp.1373-1384. ⟨10.1038/ng.3916⟩. ⟨inserm-02466466⟩
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