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Sims, Rebecca; Lee, Sven J. van der; Naj, Adam C.; Bellenguez, Celine; 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; Noethen, Markus M.; White, Charles C.; Hamilton-Nelson, Kara L.; Epelbaum, Jacques; Maier, Wolfgang; Choi, Seung-Hoan; Beecham, Gary W.; Dulary, Cecile; Herms, Stefan; Smith, Albert V.; Funk, Cory C.; Derbois, Celine; 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; Sanchez-Juan, Pascual; Morgan, Taniesha; Wolters, Frank J.; Zhao, Yi; Sanchez Garcia, Florentino; Denning, Nicola; Fornage, Myriam; Malamon, John; Deniz Naranjo, Maria Candida; Majounie, Elisa; Mosley, Thomas H.; Dombroski, Beth; Wallon, David; Lupton, Michelle K.; Dupuis, Josee; 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-Garcia, 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; Henandez, Isabel; Barber, Robert C.; Scherer, Martin; Tárraga, Lluís; 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, W. T.; Fairchild, Thomas J.; Bossu, 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; Diez Fairen, Mnica; 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; Lleo, Alberto; Forte, 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; Pankratz, Vernon S.; 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.; Deerlin, Vivianna M. van; Eldik, Linda J. van; Vinters, Harry V.; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Wilhelmsen, Kirk C.; Williamson, Jennifer; Woltjer, Randall L.; Wright, Clinton B.; Yu, Chang-En; Yu, Lei; Garzia, Fabienne; Golamaully, Feroze; Septier, Gislain; Engelborghs, Sebastien; Vandenberghe, Rik; Deyn, Peter P. de; Munoz Fernadez, Carmen; Aladro Benito, Yoland; Thonberg, Hakan; Forsell, Charlotte; Lilius, Lena; Kinhult-Stahlbom, 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, Maria 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; Clarimon, 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; 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-Francois; DeStefano, Anita L.; Ortega-Cubero, Sara; Hakonarson, Hakon; Campion, Dominique; Boada, Merce; Kauwe, John Keoni; Farrer, Lindsay A.; Broeckhoven, Christine van; Ikram, M. Arfan; Jones, Lesley; Haines, Jonathan L.; Tzourio, Christophe; Launer, Lenore J.; Escott-Price, Valentina; Mayeux, Richard P.; Deleuze, Jean-Francois; 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 und Schellenberg, Gerard D. (2017): Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. In: Nature Genetics, Bd. 49, Nr. 9: S. 1373-1384

Volltext auf 'Open Access LMU' nicht verfügbar.

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 x 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 x 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 x 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 x 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 x 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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