Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Creators: name: Taylor, Sarah
name: Craig, David
name: Qu, Liming
name: Haines, Jonathan L.
name: Morgan, Taniesha
name: Sager, Mark A.
name: Jun, Gyungah
name: Beiser, Alexa S.
name: St George-Hyslop, Peter
name: Levey, Allan I.
name: Vellas, Bruno
name: Collinge, John
name: Himali, Jayanadra J.
name: Katz, Mindy J.
name: Frank-García, Ana
name: Thonberg, Hakan
name: Grenier-Boley, Benjamin
name: Emilsson, Valur
name: Chouraki, Vincent
name: Jarvik, Gail P.
name: Rotter, Jerome I.
name: Nacmias, Benedetta
name: Chapman, Jade
name: Coto, Eliecer
name: Eiriksdottir, Gudny
name: Burgess, Jeremy D.
name: Tsolaki, Magda
name: Saykin, Andrew J.
name: Clarimón, Jordi
name: Hartmann, Annette M.
name: Beekly, Duane
name: Peters, Oliver
name: Fairén, Mònica Díez
name: Brayne, Carol
name: Bras, Jose
name: Zhao, Yi
name: Riemenschneider, Matthias
name: Corcoran, Chris
name: Norton, Maria
name: Ikram, M Arfan
name: Gudnason, Vilmundur
name: Wallon, David
name: Serpente, Maria
name: Septier, Gislain
name: Atwood, Craig S.
name: Yu, Chang-En
name: Sorbi, Sandro
name: Carlsson, Cynthia M.
name: McCormick, Wayne C.
name: Urbano, Maria
name: Galasko, Douglas R.
name: Potter, Huntington
name: Raj, Ashok
name: Dufouil, Carole
name: Reisberg, Barry
name: Braae, Anne
name: Fratiglioni, Laura
name: Forsell, Charlotte
name: Shaw, Christopher E.
name: Pastor, Pau
name: Jin, Lee-Way
name: Carrasquillo, Minerva M.
name: Epelbaum, Jacques
name: Psaty, Bruce M.
name: McDavid, Andrew N.
name: Lilius, Lena
name: Ramirez, Alfredo
name: Berr, Claudine
name: Green, Robert C.
name: Riedel-Heller, Steffi
name: Kornhuber, Johannes
name: Heilmann-Heimbach, Stefanie
name: Kauwe, John Keoni
name: Dunstan, Melanie
name: Miller, Bruce L.
name: McKee, Ann C.
name: Van Broeckhoven, Christine
name: Harold, Denise
name: Turton, James
name: Brookes, Keeley
name: Owen, Michael J.
name: Brown, Kristelle
name: Dick, Malcolm
name: Pilotto, Alberto
name: Hill, Matt
name: Carney, Regina M.
name: Thomas, Rhodri
name: Barber, Imelda S.
name: Gearing, Marla
name: Brody, Jennifer A
name: Scarpini, Elio
name: Graff, Caroline
name: Pierce, Aimee
name: Miller, Joshua W.
name: Ruiz, Agustin
name: Hofman, Albert
name: Seeley, William W.
name: Hyman, Bradley T.
name: Schellenberg, Gerard D.
name: Campion, Dominique
name: Patel, Yogen
name: Welsh-Bohmer, Kathleen A.
name: Martiniuk, Frank
name: Moreno-Grau, Sonia
name: Funk, Cory C.
name: Hamilton-Nelson, Kara L.
name: Cribbs, David H.
name: Chakrabarty, Paramita
name: Keller, Lina
name: Golde, Todd E.
name: Cao, Chuanhai
name: Petersen, Ronald C.
name: Evans, Denis A.
name: Leverenz, James B.
name: Frosch, Matthew P.
name: Laferla, Frank M.
name: Pericak-Vance, Margaret A.
name: Woltjer, Randall L.
name: Smith, Albert V.
name: Rogaeva, Ekaterina
name: Fenoglio, Chiara
name: Lyketsos, Constantine G.
name: Sussams, Rebecca
name: Kamboh, M Ilyas
name: Becker, James T.
name: Mayeux, Richard
name: Raybould, Rachel
name: Alvarez, Victoria
name: Yu, Lei
name: O'Bryant, Sid
name: Kim, Ronald
name: Vinters, Harry V.
name: Aspelund, Thor
name: Lieberman, Andrew P.
name: Vardarajan, Badri N.
name: Tzourio, Christophe
name: Tsuang, Debby W.
name: Albert, Marilyn S.
name: Hodges, Angela
name: Honig, Lawrence S.
name: Sonnen, Joshua A.
name: Hughes, Joseph T.
name: Sacchinelli, Eleonora
name: Pankratz, Vernon S.
name: Koivisto, Anne Maria
name: Sleegers, Kristel
name: Dickson, Dennis W
name: Vronskaya, Maria
name: Mead, Simon
name: Rosenberg, Roger N.
name: Boccardi, Virginia
name: Graff-Radford, Neill R.
name: Sotolongo-Grau, Oscar
name: Maier, Wolfgang
name: Gerrish, Amy
name: Peskind, Elaine
name: O'Donnell, Christopher J.
name: Carroll, Steven L.
name: Masullo, Carlo
name: Garcia, Florentino Sanchez
name: Sano, Mary
name: Schmidt, Reinhold
name: Vonsattel, Jean Paul
name: Raskind, Murray
name: McCurry, Susan M.
name: Reitz, Christiane
name: Dermecourt, Vincent
name: Hannequin, Didier
name: Lynch, Aoibhinn
name: Adams, Perrie M.
name: Gill, Michael
name: Ahmad, Shahzad
name: Bacq, Delphine
name: Stern, Robert A.
name: Burke, James R.
name: Hakonarson, Hakon
name: Naj, Adam C
name: Fallon, Kenneth B.
name: De Deyn, Peter P.
name: Masliah, Eliezer
name: Brundin, Rosemarie
name: Dubois, Bruno
name: Schneider, Lon S.
name: Morris, John C.
name: Holmes, Clive
name: Lunetta, Kathryn L.
name: Duara, Ranjan
name: Boeve, Bradley F.
name: Larson, Eric B.
name: Fornage, Myriam
name: Lopez, Oscar L.
name: Lupton, Michelle K.
name: Winslow, Ashley R.
name: Giegling, Ina
name: Spina, Salvatore
name: Nöthen, Markus M.
name: Paulson, Henry L.
name: Uphill, James
name: Blacker, Deborah
name: Arnold, Steven E.
name: Jakobsdottir, Johanna
name: Li, Hongdong
name: Choi, Seung-Hoan
name: Arcaro, Marina
name: Dupuis, Josée
name: Schmidt, Helena
name: Majounie, Elisa
name: Powell, John
name: Pichler, Sabrina
name: Thornton-Wells, Tricia A.
name: Foroud, Tatiana M.
name: Carlson, Chris S.
name: Jessen, Frank
name: Boerwinkle, Eric
name: Younkin, Steven G.
name: Amin, Najaf
name: Van Deerlin, Vivianna M.
name: Ferris, Steven
name: Leber, Markus
name: Thomas, Charlene
name: Johnston, Janet
name: Whitehead, Patrice
name: Dombroski, Beth
name: Kaye, Jeffrey A.
name: Royall, Donald R.
name: Engelborghs, Sebastien
name: Spalletta, Gianfranco
name: Hoffmann, Per
name: Marshall, Rachel
name: Orfei, Maria Donata
name: Bellenguez, Céline
name: Beach, Thomas G.
name: Haapasalo, Annakaisa
name: Perry, William
name: Cecchetti, Roberta
name: Blesa, Rafael
name: Bullido, María J.
name: Daniele, Antonio
name: Fievet, Nathalie
name: Troncoso, Juan C.
name: Chui, Helena C.
name: Benito, Yoland Aladro
name: Grove, Megan L.
name: Lord, Jenny
name: Daniilidou, Makrina
name: Cairns, Nigel J.
name: Cupples, L Adrienne
name: Tanzi, Rudolph E.
name: Lipton, Richard B.
name: Galimberti, Daniela
name: Parisi, Joseph E.
name: Garcia, Melissa E.
name: Ciaramella, Antonio
name: Mesulam, Marsel
name: Bigio, Eileen H.
name: Tschanz, Joann
name: Fernadez, Carmen Muñoz
name: Giedraitis, Vilmantas
name: Van Eldik, Linda J.
name: Weintraub, Sandra
name: Karydas, Anna
name: Burns, Jeffrey M.
name: Van Duijn, Cornelia M.
name: Farrer, Lindsay A.
name: Derbois, Céline
name: Combarros, Onofre
name: Growdon, John H.
name: Satizabal, Claudia L.
name: Escott-Price, Valentina
name: Ritchie, Karen
name: Kinhult-Stählbom, Anne
name: Braddel, Amy
name: Barnes, Lisa L.
name: Diaz, Carolina Ceballos
name: Morgan, Kevin
name: Kramer, Joel H.
name: Ingelsson, Martin
name: Williams, Julie
name: Boxer, Adam
name: Caffarra, Paolo
name: Aguilar, Miquel
name: Barral, Sandra
name: Doody, Rachelle S.
name: Hiltunen, Mikko
name: Ortega-Cubero, Sara
name: Concari, Letizia
name: Passmore, Peter
name: Huebinger, Ryan M.
name: Sánchez-Juan, Pascual
name: Fardo, David W.
name: Olichney, John M.
name: Dichgans, Martin
name: Lambert, Jean-Charles
name: Gu, Wei
name: Hardy, John
name: Gallo, Maura
name: Lannfelt, Lars
name: Allen, Mariet
name: Yang, Qiong
name: Behrens, Timothy W.
name: Uitterlinden, Andre G.
name: Adams, Hieab H
name: Henández, Isabel
name: Levy, Daniel
name: Cantwell, Laura B.
name: Hulette, Christine M.
name: Lin, Honghuang
name: Crocco, Elizabeth A.
name: Deleuze, Jean-François
name: Keene, C Dirk
name: De Jager, Philip L
name: Boada, Merce
name: Soininen, Hilkka
name: Olaso, Robert
name: Mayhaus, Manuel
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name: Graham, Robert R
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name: Mancuso, Michelangelo
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name: Farlow, Martin R.
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name: Badarinarayan, Nandini
name: Kukull, Walter A.
name: Price, Nathan D.
name: Hanon, Olivier
name: Tzourio, Christophe
name: Mosley, Thomas H.
name: Chen, Yuning
name: Proitsi, Petra
name: Swerdlow, Russell H.
name: Al-Chalabi, Ammar
name: Williamson, Jennifer
name: Murrell, Jill R.
name: Panza, Francesco
name: Boland, Anne
name: Wolters, Frank J
name: Rosen, Howard J.
name: Dulary, Cécile
name: Goate, Alison M.
name: Li, Shuo
name: Hampel, Harald
name: Pasquier, Florence
name: Clark, David G.
name: Schneider, Julie A.
name: Jr, W T Longstreth
name: Todd, Stephen
name: Roberson, Erik D.
name: Bird, Thomas D.
name: Lleó, Alberto
name: Bowen, James D.
name: Reisch, Joan S.
name: Fairchild, Thomas J.
name: Malamon, John
name: Bosco, Paolo
name: Garzia, Fabienne
name: Marson, Daniel C.
name: Reiman, Eric M.
name: Bossù, Paola
name: Kuzma, Amanda B.
name: Kloszewska, Iwona
name: Apostolova, Liana G.
name: Carrell, David
name: Mecocci, Patrizia
name: Ertekin-Taner, Nilufer
name: Wilhelmsen, Kirk C.
name: Miller, Carol A.
name: Ghetti, Bernardino
name: Montine, Thomas J.
name: Kilander, Lena
name: Jones, Lesley
name: Lovestone, Simon
name: Gilbert, John R.
name: Forstner, Andreas J.
name: Wang, Li-San
name: Smith, Amanda G.
name: Decarli, Charles
name: Tarraga, Lluis
name: Seshadri, Sudha
name: Rivadeneira, Fernando
name: Crane, Paul K.
name: Helisalmi, Seppo
name: Squassina, Alessio
name: Heun, Reinhard
name: Bonuccelli, Ubaldo
name: Amouyel, Philippe
name: Ringman, John M.
name: Destefano, Anita L.
name: Myers, Amanda J.
name: Meggy, Alun
name: Van Der Lee, Sven J
name: White, Charles C.
name: Lah, James J.
name: McGuinness, Bernadette
name: Rubinsztein, David C
name: Bruni, Amalia Cecilia
name: Seripa, Davide
name: Denning, Nicola
name: Baldwin, Clinton T.
name: Caltagirone, Carlo
name: Huentelman, Matthew J.
name: Albin, Roger L.
name: Rujescu, Dan
name: Solfrizzi, Vincenzo
name: Bennett, David A.
name: Harrell, Lindy E.
name: Herms, Stefan
name: Faber, Kelley M.
name: Geschwind, Daniel H.
name: Asthana, Sanjay
name: Beecham, Gary W.
name: Barber, Robert C.
name: Fortea, Juan
name: Poon, Wayne W.
name: Jian, Xueqiu
name: Moebus, Susanne
name: O'Donovan, Michael C.
name: Abner, Erin
name: Fitzpatrick, Annette L.
name: Mukherjee, Shubhabrata
name: Wu, Chuang-Kuo
name: Lawlor, Brian
name: Guerreiro, Rita
name: Vandenberghe, Rik
name: Sims, Rebecca
name: Kunkle, Brian W.
name: Dartigues, Jean-François
name: Munger, Ron
name: Medway, Christopher
name: Wingo, Thomas S.
name: Li, Ge
name: Scherer, Martin
name: Cruchaga, Carlos
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2017

description: We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped 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, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development.