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

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

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669039/
No data is associated with this publication.
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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