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

Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199, ARUK Consortium, van der Lee, Sven J., Naj, Adam C., Bellenguez, Céline, Badarinarayan, Nandini ORCID: https://orcid.org/0000-0002-6944-748X, 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, Sanchez Garcia, Florentino, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa ORCID: https://orcid.org/0000-0003-2800-1091, 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 Jr, W. T., 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, Díez Fairén, Mònica, 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, Donata Orfei, Maria, 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., Ceballos Diaz, Carolina, 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., Vonsatte, 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 ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, 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, Jager, Philip L De, 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 ORCID: https://orcid.org/0000-0002-3007-4612, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Holmans, Peter A. ORCID: https://orcid.org/0000-0003-0870-9412, Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Schellenberg, Gerard D., GERAD/PERADES, CHARGE, ADGC and EADI 2017. Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics 49 , pp. 1373-1384. 10.1038/ng.3916

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine Neuroscience and Mental Health Research Institute (NMHRI) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature
ISSN:	1061-4036
Date of First Compliant Deposit:	1 March 2017
Date of Acceptance:	16 June 2016
Last Modified:	14 Dec 2023 16:53
URI:	https://orca.cardiff.ac.uk/id/eprint/98651

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