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