Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease - Inserm - Institut national de la santé et de la recherche médicale 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 (63) , Patrizia Mecocci (67) , Gudny Eiriksdottir (5) , Paul Crane (34) , Florence Pasquier (68) , Virginia Boccardi (69) , Isabel Henández (13) , Robert Barber (70) , Martin Scherer (71) , Lluis Tarraga (13) , Perrie Adams (72) , Markus Leber (73) , Yuning Chen (74) , Marilyn Albert (75) , Steffi Riedel-Heller (76) , Valur Emilsson (77) , Duane Beekly (34) , Anne Braae (45) , Reinhold Schmidt (78) , Deborah Blacker (79) , Carlo Masullo (80) , Helena Schmidt (81) , Rachelle Doody (82) , Gianfranco Spalletta (82) , W T Longstreth Jr (34) , Thomas Fairchild (83) , Paola Bossù (84) , Oscar López (85) , Matthew P Frosch (86) , Eleonora Sacchinelli (84) , Bernardino Ghetti (87) , Qiong Yang (88) , Ryan Huebinger (72) , Frank Jessen (78) , Shuo Li (89) , M Ilyas Kamboh (90) , Oscar Sotolongo-Grau (13) , Mindy Katz (91) , Chris Corcoran (92) , Melanie Dunstan (1) , Amy Braddel (1) , Charlene Thomas (1) , Alun Meggy (1) , Rachel Marshall (1) , Amy Gerrish (1) , Jade Chapman (1) , Miquel Aguilar (93, 94) , Sarah Taylor (1) , Matt Hill (1) , Mònica Díez Fairén (93, 57) , Angela Hodges (95) , Bruno Vellas (96) , Hilkka Soininen (19) , Iwona Kloszewska (97) , Makrina Daniilidou (98) , James Uphill (99) , Yogen Patel (95) , Joseph Hughes (95) , Jenny Lord (45) , James Turton (45) , Annette M. Hartmann (26) , Roberta Cecchetti (53) , Chiara Fenoglio (100) , Maria Serpente (101) , Marina Arcaro (101) , Carlo Caltagirone (102) , Maria Donata Orfei (84) , Antonio Ciaramella (84) , Sabrina Pichler (103) , Manuel Mayhaus (103) , Wei Gu , Alberto Lleó (57, 104) , Juan Fortea (57, 104) , Rafael Blesa (57, 104) , Imelda Barber (45) , Keeley Brookes (45) , Chiara Cupidi (105) , Raffaele Giovanni Maletta (105) , David Carrell (34) , Sandro Sorbi (106) , Susanne Moebus (107) , Maria Joana Urbano (108) , Alberto Pilotto (52) , Johannes Kornhuber (109) , Paolo Bosco (110) , Stephen Todd (111) , David Craig (112) , Janet Johnston (42) , Michael Gill (113) , Brian Lawlor (114) , Aoibhinn Lynch (42) , Nick Fox (115) , John Hardy (116) , Roger Albin (117) , Liana G Apostolova (118) , Steven Arnold (3) , Sanjay Asthana (119) , Craig Atwood (119) , Clinton Baldwin (25) , Lisa L Barnes (120) , Sandra Barral (121) , Thomas Beach (122) , James Becker (123) , Eileen Bigio (124) , Thomas Bird (34) , Bradley Boeve (125) , James Bowen (126) , Adam Boxer (127) , James Burke (128) , Jeffrey Burns (129) , Joseph D. Buxbaum (130) , Nigel Cairns (131) , Chuanhai Cao (132) , Chris Carlson (133) , Cynthia Carlsson (119) , Regina Carney (43) , Minerva Carrasquillo (50) , Steven Carroll (134) , Carolina Ceballos Diaz (59) , Helena Chui (135) , David Clark (136) , David Cribbs (137) , Elizabeth Crocco (43) , Charles Decarli (138) , Malcolm Dick (139) , Ranjan Duara (140) , Denis Evans (141) , Kelley Faber (142) , Kenneth Fallon (143) , David Fardo (144) , Martin Farlow (142) , Steven Ferris (145) , Tatiana Foroud (146) , Douglas Galasko (147) , Marla Gearing (148) , Daniel H. Geschwind (149) , John Gilbert (43) , Neill Graff-Radford (50) , Robert Green (150) , John Growdon (151) , Ronald Hamilton (90) , Lindy Harrell (143) , Lawrence Honig (18) , Matthew Huentelman (152) , Christine Hulette (128) , Bradley T. Hyman (153) , Gail Jarvik (34) , Erin Abner (144) , Lee-Way Jin (154) , Gyungah Jun (25) , Anna Karydas (127) , Jeffrey Kaye (155) , Ronald Kim (139) , Neil Kowall (25) , Joel Kramer (127) , Frank Laferla (139) , James Lah (148) , James Leverenz (156) , Allan Levey (157) , Ge Li (158) , Andrew Lieberman (117) , Kathryn Lunetta (25) , Constantine Lyketsos (159) , Daniel Marson (143) , Frank Martiniuk (145) , Deborah Mash (160) , Eliezer Masliah (161) , Wayne Mccormick (34) , Susan Mccurry (34) , Andrew Mcdavid (133) , Ann C Mckee (31) , Marsel Mesulam (124) , Bruce Miller (162) , Carol Miller (135) , Joshua Miller (163) , John Morris (131) , Jill Murrell (164) , Amanda Myers (43) , Sid O'Bryant (165) , John Olichney (163) , Vernon Pankratz (166) , Joseph Parisi (125) , Henry Paulson (117) , William Perry (43) , Elaine Peskind (34) , Aimee Pierce (139) , Wayne Poon (167) , Huntington Potter (168) , Joseph Quinn (169) , Ashok Raj (132) , Murray Raskind (34) , Barry Reisberg (145) , Christiane Reitz (18) , John Ringman (170) , Erik Roberson (143) , Ekaterina Rogaeva (171) , Howard Rosen (127) , Roger Rosenberg (72) , Mark Sager (119) , Andrew Saykin (172) , Julie A Schneider (120) , Lon S Schneider (173) , William Seeley (127) , Amanda Smith (132) , Joshua Sonnen (34) , Salvatore Spina (174) , Robert Stern (31) , Russell Swerdlow (129) , Rudolph E. Tanzi (175) , Tricia Thornton-Wells (176) , John Q Trojanowski (177) , Juan Troncoso (78) , Vivianna van Deerlin (177) , Linda van Eldik (144) , Harry V. Vinters (178) , Jean Paul Vonsattel (18) , Sandra Weintraub (124) , Kathleen Welsh-Bohmer (128) , Kirk Wilhelmsen (179) , Jennifer Williamson (18) , Thomas Wingo (148) , Randall Woltjer (155) , Clinton Wright (43) , Chang-En Yu (180) , Lei Yu (120) , Fabienne Garzia (181) , Feroze Golamaully (181) , Gislain Septier (181) , Sebastien Engelborghs (182) , Rik Vandenberghe (12) , Peter de Deyn (183) , Carmen Muñoz Fernadez (36) , Yoland Aladro Benito (36) , Hakan Thonberg (184) , Charlotte Forsell (185, 184) , Lena Lilius (185, 184) , Anne Kinhult-Stählbom (185, 184) , Lena Kilander (63) , Rosemarie Brundin (63) , Letizia Concari (60, 61) , Seppo Helisalmi (186, 19) , Anne Maria Koivisto (186, 19) , Annakaisa Haapasalo (186, 19) , Vincent Dermecourt (187) , Nathalie Fievet (4) , Olivier Hanon (188) , Carole Dufouil (189) , Alexis Brice (190) , Karen Ritchie (191) , Bruno Dubois (192) , Jayanadra Himali (31) , C Dirk Keene (34) , Joann Tschanz (92) , Annette Fitzpatrick (193) , Walter Kukull (34) , Maria Norton (92) , Thor Aspelund (77) , Eric Larson (34) , Ron Munger (92) , Jerome Rotter (194) , Richard Lipton (195) , María Bullido (196, 57, 197) , Albert Hofman (198) , Thomas Montine (34) , Eliecer Coto (199) , Eric Boerwinkle (82) , Ronald Petersen (125) , Victoria Alvarez (199) , Fernando Rivadeneira (200) , Eric Reiman (201, 202, 203) , Maura Gallo (105) , Christopher O'Donnell (54) , Joan Reisch (72) , Amalia Cecilia Bruni (105) , Donald Royall (204) , Martin Dichgans (78) , Mary Sano (205) , Daniela Galimberti (206) , Peter St George-Hyslop (207) , Elio Scarpini (206) , Debby Tsuang (34, 208) , Michelangelo Mancuso (209) , Ubaldo Bonuccelli (209) , Ashley Winslow (210) , Antonio Daniele (211) , Chuang-Kuo Wu (212) , Oliver Peters (172) , Benedetta Nacmias (106) , Matthias Riemenschneider (213) , Reinhard Heun (214) , Carol Brayne (215) , David C. Rubinsztein (216) , Jose Bras (217) , Rita Guerreiro (217) , Ammar Al-Chalabi (218) , Christopher Shaw (219) , John Collinge (99) , David Mann (220) , Magda Tsolaki (221) , Jordi Clarimón (57, 222) , Rebecca Sussams (223) , Simon Lovestone (224) , Michael O'Donovan (1) , Michael Owen (225) , Timothy Behrens (226) , Simon Mead (227) , Alison Goate (228) , André G. Uitterlinden (229) , Clive Holmes (208) , Carlos Cruchaga (230) , Martin Ingelsson (63) , David A Bennett (120) , John Powell (95) , Todd Golde (59) , Caroline Graff (184) , Philip L de Jager (231) , Kevin Morgan (232) , Nilufer Ertekin-Taner (233) , Onofre Combarros (57) , Bruce Psaty (34, 57) , Peter Passmore (112) , Steven Younkin (50) , Claudine Berr (191) , Vilmundur Gudnason (234) , Dan Rujescu (235) , Dennis Dickson (50) , Jean-François Dartigues (236) , Anita Destefano (25) , Sara Ortega-Cubero (57) , Hakon Hakonarson (237) , Dominique Campion (40) , Merce Boada (238) , John Keoni Kauwe (13) , Lindsay Farrer (31) , Christine van Broeckhoven (239) , M Arfan Ikram (2) , Lesley Jones (240) , Jonathan Haines (241) , Christophe Tzourio (242) , Lenore Launer (65) , Valentina Escott-Price (243) , Richard P. Mayeux (244) , Jean-François Deleuze (15) , Najaf Amin (245) , Peter Holmans (243) , Margaret Pericak-Vance (6) , Philippe Amouyel (4) , Cornelia M. van Duijn (198) , Alfredo Ramírez (246) , Li-San Wang (247) , Jean-Charles Lambert (4) , Sudha Seshadri (31, 248) , Julie Williams (225) , 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 Institute of Gerontology and Geriatrics
68 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
69 Geriatric Medicine and Metabolic Diseases
70 Departments of Nuclear Medicine
71 University Medical Centre Hamburg-Eppendorf [Hamburg, Germany]
72 University of Texas Southwestern Medical Center [Dallas]
73 University of Cologne
74 LERIA - Laboratoire d'Etudes et de Recherche en Informatique d'Angers
75 JHU - Johns Hopkins University
76 Leipzig University / Universität Leipzig
77 University of Iceland [Reykjavik]
78 Metacohorts Consortium
79 Harvard School of Public Health
80 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
81 Medical University Graz
82 BCM - Baylor College of Medicine
83 University of North Texas Health Science Center [Fort Worth]
84 IRCCS - Santa Lucia Foundation
85 Nextel S.A. [Bilbao]
86 Massachusetts General Hospital [Boston]
87 Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center
88 JISAO - Joint Institute for the Study of the Atmosphere and Ocean
89 Beijing University of Technology
90 PITT - University of Pittsburgh
91 Saul B. Korey Department of Neurology
92 USU - Utah State University
93 Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain]
94 Hospital Universitario Mutua de Terrassa
95 King‘s College London
96 Département de neurologie [Montpellier]
97 MUL - Medical University of Łódź
98 University of Leicester
99 Department of Neurodegenerative Diseases
100 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
101 UNIMI - Università degli Studi di Milano = University of Milan
102 Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome]
103 UKS - Saarland University Hospital
104 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
105 CRN - ASP Catanzaro - Regional Neurogenetic Centre [Lamezia Terme, Italy]
106 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
107 Institute for Medical Informatics, Biometry and Epidemiology
108 Universidade do Porto = University of Porto
109 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
110 Experimental and Clinical Pharmacology
111 Ageing Group, Centre for Public Health
112 QUB - Queen's University [Belfast]
113 St. James Hospital and Trinity College [Dublin, Ireland]
114 School of Medicine [Dublin]
115 University of Sheffield [Sheffield]
116 Lancaster University
117 University of Michigan [Ann Arbor]
118 David Geffen School of Medicine [Los Angeles]
119 University of Wisconsin-Madison
120 Rush Alzheimer Disease Center [Chicago, IL, États-Unis]
121 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
122 Cardiff School of Engineering
123 Department of Psychiatry [Pittsburgh]
124 Feinberg School of Medicine
125 Mayo Clinic [Rochester]
126 Swedish Medical Center [Seattle, WA, USA]
127 UC San Francisco - University of California [San Francisco]
128 Duke University [Durham]
129 University of Kansas Medical Center [Kansas City, KS, USA]
130 Laboratory of Molecular Neuropsychiatry
131 WUSTL - Washington University in Saint Louis
132 USF - University of South Florida [Tampa]
133 FHCRC - Fred Hutchinson Cancer Research Center [Seattle]
134 MUSC - Medical University of South Carolina [Charleston]
135 USC - University of Southern California
136 LANL - Los Alamos National Laboratory
137 CBD - Centre de biologie du développement
138 UCDavis-Neuro - Neurology Department, University of California, Davis
139 UC Irvine - University of California [Irvine]
140 Mount Sinai Medical Center
141 Rush University Medical Center [Chicago]
142 Indiana State University
143 UAB - University of Alabama at Birmingham [ Birmingham]
144 UK - University of Kentucky
145 NYU - New York University [New York]
146 Department of Medical and Molecular Genetics
147 Department of Epidemiology and biostatistics
148 Emory University [Atlanta, GA]
149 Department of Neurology
150 BWH - Brigham & Women’s Hospital [Boston]
151 HMS - Harvard Medical School [Boston]
152 Department of Medical Genetics
153 Alzheimer Disease Research Laboratory
154 UC Davis - University of California [Davis]
155 OHSU - Oregon Health and Science University [Portland]
156 Cleveland Clinic
157 Department of Neurology
158 LISTIC - Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance
159 Department of Psychiatry
160 Douglas Mental Health University Institute [Montréal]
161 Department of neurosciences
162 Department of Physics and Astronomy [Fort Worth]
163 CS - UC Davis - Department of Computer Science [Univ California Davis]
164 Indiana University School of Medicine
165 IAADR - Institute for Aging and Alzheimer’s Disease Research [Fort Worth]
166 Department of Laboratory Medicine and Pathology
167 Institute for Memory Impairments and Neurological Disorders [Irvine]
168 University of Colorado Anschutz [Aurora]
169 Department of Neurology
170 UCLA - University of California [Los Angeles]
171 Tanz Center Research in Neurodegenerative Diseases [Toronto]
172 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
173 Keck School of Medicine [Los Angeles]
174 Indiana University [South Bend]
175 Massachusetts General Hospital
176 Novartis Institutes for Biomedical Research [Cambridge, MA, USA]
177 Perelman School of Medicine
178 Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology
179 UNC - University of North Carolina [Chapel Hill]
180 Department of Medicine
181 IG - Institut de Génomique d'Evry
182 UA - University of Antwerp
183 Institute Born-Bunge
184 Karolinska Institutet [Stockholm]
185 Karolinska University Hospital [Stockholm]
186 University of Kuopio
187 CMRR - Centre Mémoire de Ressources et de Recherche [Lille-Bailleul]
188 Dpt Gériatrie [CHU Broca]
189 Neuroépidémiologie
190 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
191 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
192 GRC 21 - APM - Groupe de recherche clinique Alzheimer Precision Medicine
193 Department of Epidemiology, University of Washington
194 School of Medicine [Los Angeles]
195 Albert Einstein College of Medicine [New York]
196 IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain]
197 IFT - Instituto de Física Teórica UAM/CSIC
198 Department of Internal Medicine
199 University of Central Asturias [Oviedo, Spain]
200 Department of Epidemiology
201 Translational Genomics Research Institute [Phoenix, AZ, USA]
202 University of Arizona
203 Banner Alzheimer's Institute
204 University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA]
205 Mount Sinai School of Medicine
206 Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico
207 Centre for Research in Neurodegenerative Diseases
208 VA Puget Sound Health Care System/GRECC [Seattle, WA, USA]
209 University of Pisa - Università di Pisa
210 Pfizer Worldwide Research and Development [Cambridge, MA, USA]
211 Unicatt - Università cattolica del Sacro Cuore [Piacenza e Cremona]
212 Texas Tech University Health Sciences Center
213 Saarland University [Saarbrücken]
214 Universität Bonn = University of Bonn
215 Department of Public Health and Primary Care
216 CIMR - Cambridge Institute for Medical Research
217 Department of Molecular Neurosciences
218 Institute of Psychiatry
219 UBC - University of British Columbia
220 the Clinical Neuroscience Research Group
221 Aristotle University of Thessaloniki
222 University of Barcelona
223 University of Southampton
224 POWIC - Department of Psychiatry [Oxford]
225 School of Psychology [Cardiff University]
226 Department of Medical Sciences
227 UCL Queen Square Institute of Neurology
228 Department of Psychiatry
229 Netherlands Genomics Initiative
230 School of Medecine
231 CTCN - Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis]
232 School of Life Sciences
233 Department of Neuroscience
234 Icelandic Heart Association
235 Klinik für Psychiatrie
236 Epidémiologie et Biostatistique [Bordeaux]
237 The Center for Applied Genomics
238 Clínica Universidad de Navarra [Pamplona]
239 Neurodegenerative Brain Diseases Group
240 MRC Centre for Neuropsychiatric Genetics and Genomics
241 BYU - Brigham Young University
242 ISPED - Institut de Santé Publique, d'Epidémiologie et de Développement
243 Cardiff University
244 The Gertrude H Sergivesky Center
245 Genetic Epidemiology Unit
246 Section of Clinical and Molecular Neurogenetics
247 University of Pennsylvania - Department of Pathology & Laboratory Medecine
248 Framingham Heart Study [Framingham, MA, USA]
Anne Boland
Stefan Herms
Andreas Forstner
Michelle Lupton
  • Fonction : Auteur
Xue Wang
  • Fonction : Auteur
  • PersonId : 886838
Lars Lannfelt
  • Fonction : Auteur
Gianfranco Spalletta
Paola Bossù
Mindy Katz
  • Fonction : Auteur
  • PersonId : 948390
Bruno Vellas
Hilkka Soininen
Joseph Hughes
Wei Gu
  • Fonction : Auteur
Stephen Todd
  • Fonction : Auteur
  • PersonId : 899288
David Craig
  • Fonction : Auteur
  • PersonId : 887941
Janet Johnston
  • Fonction : Auteur
Aoibhinn Lynch
  • Fonction : Auteur
Nick Fox
  • Fonction : Auteur
  • PersonId : 893842
John Hardy
  • Fonction : Auteur
Thomas Beach
  • Fonction : Auteur
  • PersonId : 1051258
David Cribbs
  • Fonction : Auteur
  • PersonId : 1037132
James Leverenz
  • Fonction : Auteur
Constantine Lyketsos
  • Fonction : Auteur
  • PersonId : 909833
John Morris
Peter de Deyn
  • Fonction : Auteur
  • PersonId : 921857
Lena Kilander
  • Fonction : Auteur
Carole Dufouil
  • Fonction : Auteur
  • PersonId : 843041
Eric Larson
  • Fonction : Auteur
  • PersonId : 968779
Ron Munger
  • Fonction : Auteur
Carol Brayne
  • Fonction : Auteur
  • PersonId : 948386
Ammar Al-Chalabi
  • Fonction : Auteur
  • PersonId : 896934
Magda Tsolaki
  • Fonction : Auteur
  • PersonId : 887860
Michael Owen
Alison Goate
Caroline Graff
  • Fonction : Auteur
  • PersonId : 889097
Peter Passmore
  • Fonction : Auteur
  • PersonId : 887943
Hakon Hakonarson
Dominique Campion
  • Fonction : Auteur
  • PersonId : 863253
Jean-François Deleuze
  • Fonction : Auteur
  • PersonId : 1015006
Peter Holmans
  • Fonction : Auteur

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.
Fichier sous embargo
Fichier sous embargo
Date de visibilité indéterminée
Loading...

Dates et versions

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

Identifiants

Citer

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⟩
411 Consultations
3 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More