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

Publication Type:

Journal Article

Authors:

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; Jr, W T Longstreth; 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; 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; Peters, Oliver; Nacmias, Benedetta; Riemenschneider, Matthias; Heun, Reinhard; Brayne, Carol; Rubinsztein, David C; Bras, Jose; Guerreiro, Rita; Al-Chalabi, Ammar; Shaw, Christopher E; Collinge, John; Mann, David; Tsolaki, Magda; Clarimón, Jordi; Sussams, Rebecca; Lovestone, Simon; O'Donovan, Michael C; Owen, Michael J; Behrens, Timothy W; Mead, Simon; Goate, Alison M; Uitterlinden, Andre G; Holmes, Clive; Cruchaga, Carlos; Ingelsson, Martin; Bennett, David A; Powell, John; Golde, Todd E; Graff, Caroline; De Jager, Philip L; Morgan, Kevin; Ertekin-Taner, Nilufer; Combarros, Onofre; Psaty, Bruce M; Passmore, Peter; Younkin, Steven G; Berr, Claudine; Gudnason, Vilmundur; Rujescu, Dan; Dickson, Dennis W; Dartigues, Jean-François; Destefano, Anita L; Ortega-Cubero, Sara; Hakonarson, Hakon; Campion, Dominique; Boada, Merce; Kauwe, John Keoni; Farrer, Lindsay A; Van Broeckhoven, Christine; Ikram, M Arfan; Jones, Lesley; Haines, Jonathan L; Tzourio, Christophe; Launer, Lenore J; Escott-Price, Valentina; Mayeux, Richard; Deleuze, Jean-François; Amin, Najaf; Holmans, Peter A; Pericak-Vance, Margaret A; Amouyel, Philippe; van Duijn, Cornelia M; Ramirez, Alfredo; Wang, Li-San; Lambert, Jean-Charles; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D

Source:

Nature genetics (2017)

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.