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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 Olaso 15 Per Hoffmann 16 Megan Grove 17 Badri Vardarajan 18 Mikko Hiltunen 19 Markus 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 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 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 Longstreth Jr 34 Thomas Fairchild 84 Paola Bossù 85 Oscar López 86 Matthew 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 98 Iwona Kloszewska 99 Makrina Daniilidou 100 James Uphill 101 Yogen Patel 96 Joseph Hughes 96 Jenny Lord 45 James Turton 45 Annette Hartmann 26 Roberta Cecchetti 53 Chiara Fenoglio 102 Maria Serpente 103 Marina Arcaro 103 Carlo Caltagirone 104 Maria Donata Orfei 85 Antonio Ciaramella 85 Sabrina Pichler 105 Manuel Mayhaus 105 Wei Gu 106 Alberto Lleó 57, 107 Juan Fortea 57, 107 Rafael Blesa 57, 107 Imelda Barber 45 Keeley Brookes 45 Chiara Cupidi 108 Raffaele Giovanni Maletta 108 David Carrell 34 Sandro Sorbi 109 Susanne Moebus 110 Maria Urbano 111 Alberto Pilotto 52 Johannes Kornhuber 112 Paolo Bosco 113 Stephen Todd 114 David Craig 115 Janet Johnston 42 Michael Gill 116 Brian Lawlor 117 Aoibhinn Lynch 42 Nick Fox 118 John Hardy 119 Roger Albin 120 Liana Apostolova 121 Steven Arnold 3 Sanjay Asthana 122 Craig Atwood 122 Clinton Baldwin 25 Lisa Barnes 123 Sandra Barral 124 Thomas Beach 125 James Becker 126 Eileen Bigio 127 Thomas Bird 34 Bradley Boeve 128 James Bowen 129 Adam Boxer 130 James Burke 131 Jeffrey Burns 132 Joseph Buxbaum 133 Nigel Cairns 134 Chuanhai Cao 135 Chris Carlson 136 Cynthia Carlsson 122 Regina Carney 43 Minerva Carrasquillo 50 Steven Carroll 137 Carolina Ceballos Diaz 59 Helena Chui 138 David Clark 139 David Cribbs 140 Elizabeth Crocco 43 Charles Decarli 141 Malcolm Dick 142 Ranjan Duara 143 Denis Evans 144 Kelley Faber 145 Kenneth Fallon 146 David Fardo 147 Martin Farlow 145 Steven Ferris 148 Tatiana Foroud 149 Douglas Galasko 150 Marla Gearing 151 Daniel Geschwind 152 John Gilbert 43 Neill Graff-Radford 50 Robert Green 153 John Growdon 154 Ronald Hamilton 91 Lindy Harrell 146 Lawrence Honig 18 Matthew Huentelman 155 Christine Hulette 131 Bradley Hyman 156 Gail Jarvik 34 Erin Abner 147 Lee-Way Jin 157 Gyungah Jun 25 Anna Karydas 130 Jeffrey Kaye 158 Ronald Kim 142 Neil Kowall 25 Joel Kramer 130 Frank Laferla 142 James Lah 151 James Leverenz 159 Allan Levey 160 Ge Li 161 Andrew Lieberman 120 Kathryn Lunetta 25 Constantine Lyketsos 162 Daniel Marson 146 Frank Martiniuk 148 Deborah Mash 163 Eliezer Masliah 164 Wayne Mccormick 34 Susan Mccurry 34 Andrew Mcdavid 136 Ann Mckee 31 Marsel Mesulam 127 Bruce Miller 165 Carol Miller 138 Joshua Miller 166 John Morris 134 Jill Murrell 167 Amanda Myers 43 Sid O'Bryant 168 John Olichney 166 Vernon Pankratz 169 Joseph Parisi 128 Henry Paulson 120 William Perry 43 Elaine Peskind 34 Aimee Pierce 142 Wayne Poon 170 Huntington Potter 171 Joseph Quinn 172 Ashok Raj 135 Murray Raskind 34 Barry Reisberg 148 Christiane Reitz 18 John Ringman 173 Erik Roberson 146 Ekaterina Rogaeva 174 Howard Rosen 130 Roger Rosenberg 73 Mark Sager 122 Andrew Saykin 175 Julie Schneider 123 Lon Schneider 176 William Seeley 130 Amanda Smith 135 Joshua Sonnen 34 Salvatore Spina 177 Robert Stern 31 Russell Swerdlow 132 Rudolph Tanzi 178 Tricia Thornton-Wells 179 John Trojanowski 180 Juan Troncoso 79 Vivianna van Deerlin 180 Linda van Eldik 147 Harry Vinters 181 Jean Paul Vonsattel 18 Sandra Weintraub 127 Kathleen Welsh-Bohmer 131 Kirk Wilhelmsen 182 Jennifer Williamson 18 Thomas Wingo 151 Randall Woltjer 158 Clinton Wright 43 Chang-En Yu 183 Lei Yu 123 Fabienne Garzia 184 Feroze Golamaully 184 Gislain Septier 184 Sebastien Engelborghs 185 Rik Vandenberghe 12 Peter de Deyn 186 Carmen Muñoz Fernadez 36 Yoland Aladro Benito 36 Hakan Thonberg 187 Charlotte Forsell 188, 187 Lena Lilius 188, 187 Anne Kinhult-Stählbom 188, 187 Lena Kilander 63 Rosemarie Brundin 63 Letizia Concari 60, 61 Seppo Helisalmi 189, 19 Anne Maria Koivisto 189, 19 Annakaisa Haapasalo 189, 19 Vincent Dermecourt 190 Nathalie Fievet 191 Olivier Hanon 192 Carole Dufouil 193 Alexis Brice 194 Karen Ritchie 195 Bruno Dubois 196 Jayanadra Himali 31 C Dirk Keene 34 Joann Tschanz 93 Annette Fitzpatrick 197 Walter Kukull 34 Maria Norton 93 Thor Aspelund 78 Eric Larson 34 Ron Munger 93 Jerome Rotter 198 Richard Lipton 199 María Bullido 200, 57, 201 Albert Hofman 202 Thomas Montine 34 Eliecer Coto 203 Eric Boerwinkle 204 Ronald Petersen 128 Victoria Alvarez 203 Fernando Rivadeneira 205 Eric Reiman 206, 207, 208 Maura Gallo 108 Christopher O'Donnell 54 Joan Reisch 73 Amalia Cecilia Bruni 108 Donald Royall 209 Martin Dichgans 79 Mary Sano 210 Daniela Galimberti 211 Peter St George-Hyslop 212 Elio Scarpini 211 Debby Tsuang 34, 213 Michelangelo Mancuso 214 Ubaldo Bonuccelli 214 Ashley Winslow 215 Antonio Daniele 216 Chuang-Kuo Wu 217 Oliver Peters 175 Benedetta Nacmias 109 Matthias Riemenschneider 218 Reinhard Heun 219 Carol Brayne 220 David Rubinsztein 221 Jose Bras 222 Rita Guerreiro 222 Ammar Al-Chalabi 223 Christopher Shaw 224 John Collinge 101 David Mann 225 Magda Tsolaki 226 Jordi Clarimón 57, 227 Rebecca Sussams 228 Simon Lovestone 229 Michael O'Donovan 1 Michael Owen 230 Timothy Behrens 231 Simon Mead 232 Alison Goate 233 André Uitterlinden 234 Clive Holmes 213 Carlos Cruchaga 235 Martin Ingelsson 63 David Bennett 123 John Powell 96 Todd Golde 59 Caroline Graff 187 Philip de Jager 236 Kevin Morgan 237 Nilufer Ertekin-Taner 238 Onofre Combarros 57 Bruce Psaty 34, 57 Peter Passmore 115 Steven Younkin 50 Claudine Berr 195 Vilmundur Gudnason 239 Dan Rujescu 240 Dennis Dickson 50 Jean-François Dartigues 241 Anita Destefano 25 Sara Ortega-Cubero 57 Hakon Hakonarson 242 Dominique Campion 40 Merce Boada 243 John Keoni Kauwe 13 Lindsay Farrer 31 Christine van Broeckhoven 244 M Arfan Ikram 2 Lesley Jones 245 Jonathan Haines 246 Christophe Tzourio 247 Lenore Launer 65 Valentina Escott-Price 248 Richard Mayeux 249 Jean-François Deleuze 15 Najaf Amin 250 Peter Holmans 248 Margaret Pericak-Vance 6 Philippe Amouyel 4 Cornelia van Duijn 202 Alfredo Ramírez 251 Li-San Wang 252 Jean-Charles Lambert 4 Sudha Seshadri 31, 253 Julie Williams 230, * Gerard Schellenberg 39, *
* Corresponding author
196 APM - Alzheimer Precision Medicine GRC n°21
CHU Pitié-Salpêtrière [AP-HP]
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.
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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, Nature Publishing Group, 2017, 49 (9), pp.1373-1384. ⟨10.1038/ng.3916⟩. ⟨inserm-02466466⟩

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