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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

  • Author(s): Kunkle, Brian W;
  • Grenier-Boley, Benjamin;
  • Sims, Rebecca;
  • Bis, Joshua C;
  • Damotte, Vincent;
  • Naj, Adam C;
  • Boland, Anne;
  • Vronskaya, Maria;
  • van der Lee, Sven J;
  • Amlie-Wolf, Alexandre;
  • Bellenguez, Céline;
  • Frizatti, Aura;
  • Chouraki, Vincent;
  • Martin, Eden R;
  • Sleegers, Kristel;
  • Badarinarayan, Nandini;
  • Jakobsdottir, Johanna;
  • Hamilton-Nelson, Kara L;
  • Moreno-Grau, Sonia;
  • Olaso, Robert;
  • Raybould, Rachel;
  • Chen, Yuning;
  • Kuzma, Amanda B;
  • Hiltunen, Mikko;
  • Morgan, Taniesha;
  • Ahmad, Shahzad;
  • Vardarajan, Badri N;
  • Epelbaum, Jacques;
  • Hoffmann, Per;
  • Boada, Merce;
  • Beecham, Gary W;
  • Garnier, Jean-Guillaume;
  • Harold, Denise;
  • Fitzpatrick, Annette L;
  • Valladares, Otto;
  • Moutet, Marie-Laure;
  • Gerrish, Amy;
  • Smith, Albert V;
  • Qu, Liming;
  • Bacq, Delphine;
  • Denning, Nicola;
  • Jian, Xueqiu;
  • Zhao, Yi;
  • Del Zompo, Maria;
  • Fox, Nick C;
  • Choi, Seung-Hoan;
  • Mateo, Ignacio;
  • Hughes, Joseph T;
  • Adams, Hieab H;
  • Malamon, John;
  • Sanchez-Garcia, Florentino;
  • Patel, Yogen;
  • Brody, Jennifer A;
  • Dombroski, Beth A;
  • Naranjo, Maria Candida Deniz;
  • Daniilidou, Makrina;
  • Eiriksdottir, Gudny;
  • Mukherjee, Shubhabrata;
  • Wallon, David;
  • Uphill, James;
  • Aspelund, Thor;
  • Cantwell, Laura B;
  • Garzia, Fabienne;
  • Galimberti, Daniela;
  • Hofer, Edith;
  • Butkiewicz, Mariusz;
  • Fin, Bertrand;
  • Scarpini, Elio;
  • Sarnowski, Chloe;
  • Bush, Will S;
  • Meslage, Stéphane;
  • Kornhuber, Johannes;
  • White, Charles C;
  • Song, Yuenjoo;
  • Barber, Robert C;
  • Engelborghs, Sebastiaan;
  • Sordon, Sabrina;
  • Voijnovic, Dina;
  • Adams, Perrie M;
  • Vandenberghe, Rik;
  • Mayhaus, Manuel;
  • Cupples, L Adrienne;
  • Albert, Marilyn S;
  • De Deyn, Peter P;
  • Gu, Wei;
  • Himali, Jayanadra J;
  • Beekly, Duane;
  • Squassina, Alessio;
  • Hartmann, Annette M;
  • Orellana, Adelina;
  • Blacker, Deborah;
  • Rodriguez-Rodriguez, Eloy;
  • Lovestone, Simon;
  • Garcia, Melissa E;
  • Doody, Rachelle S;
  • Munoz-Fernadez, Carmen;
  • Sussams, Rebecca;
  • Lin, Honghuang;
  • Fairchild, Thomas J;
  • Benito, Yolanda A;
  • Holmes, Clive;
  • Karamujić-Čomić, Hata;
  • Frosch, Matthew P;
  • Thonberg, Hakan;
  • Maier, Wolfgang;
  • Roshchupkin, Gennady;
  • Ghetti, Bernardino;
  • Giedraitis, Vilmantas;
  • Kawalia, Amit;
  • Li, Shuo;
  • Huebinger, Ryan M;
  • Kilander, Lena;
  • Moebus, Susanne;
  • Hernández, Isabel;
  • Kamboh, M Ilyas;
  • Brundin, RoseMarie;
  • Turton, James;
  • Yang, Qiong;
  • Katz, Mindy J;
  • Concari, Letizia;
  • Lord, Jenny;
  • Beiser, Alexa S;
  • Keene, C Dirk;
  • Helisalmi, Seppo;
  • Kloszewska, Iwona;
  • Kukull, Walter A;
  • Koivisto, Anne Maria;
  • Lynch, Aoibhinn;
  • Tarraga, Lluís;
  • Larson, Eric B;
  • Haapasalo, Annakaisa;
  • Lawlor, Brian;
  • Mosley, Thomas H;
  • Lipton, Richard B;
  • Solfrizzi, Vincenzo;
  • Gill, Michael;
  • Longstreth, WT;
  • Montine, Thomas J;
  • Frisardi, Vincenza;
  • Diez-Fairen, Monica;
  • Rivadeneira, Fernando;
  • Petersen, Ronald C;
  • Deramecourt, Vincent;
  • Alvarez, Ignacio;
  • Salani, Francesca;
  • Ciaramella, Antonio;
  • Boerwinkle, Eric;
  • Reiman, Eric M;
  • Fievet, Nathalie;
  • Rotter, Jerome I;
  • Reisch, Joan S;
  • Hanon, Olivier;
  • Cupidi, Chiara;
  • Andre Uitterlinden, AG;
  • Royall, Donald R;
  • Dufouil, Carole;
  • Maletta, Raffaele Giovanni;
  • de Rojas, Itziar;
  • Sano, Mary;
  • Brice, Alexis;
  • Cecchetti, Roberta;
  • George-Hyslop, Peter St;
  • Ritchie, Karen;
  • Tsolaki, Magda;
  • Tsuang, Debby W;
  • Dubois, Bruno;
  • Craig, David;
  • Wu, Chuang-Kuo;
  • Soininen, Hilkka;
  • Avramidou, Despoina;
  • Albin, Roger L;
  • Fratiglioni, Laura;
  • Germanou, Antonia;
  • Apostolova, Liana G;
  • Keller, Lina;
  • Koutroumani, Maria;
  • Arnold, Steven E;
  • Panza, Francesco;
  • Gkatzima, Olymbia;
  • Asthana, Sanjay;
  • Hannequin, Didier;
  • Whitehead, Patrice;
  • Atwood, Craig S;
  • Caffarra, Paolo;
  • Hampel, Harald;
  • Quintela, Inés;
  • Carracedo, Ángel;
  • Lannfelt, Lars;
  • Rubinsztein, David C;
  • Barnes, Lisa L;
  • Pasquier, Florence;
  • Frölich, Lutz;
  • Barral, Sandra;
  • McGuinness, Bernadette;
  • Beach, Thomas G;
  • Johnston, Janet A;
  • Becker, James T;
  • Passmore, Peter;
  • Bigio, Eileen H;
  • Schott, Jonathan M;
  • Bird, Thomas D;
  • Warren, Jason D;
  • Boeve, Bradley F;
  • Lupton, Michelle K;
  • Bowen, James D;
  • Proitsi, Petra;
  • Boxer, Adam;
  • Powell, John F;
  • Burke, James R;
  • Kauwe, John SK;
  • Burns, Jeffrey M;
  • Mancuso, Michelangelo;
  • Buxbaum, Joseph D;
  • Bonuccelli, Ubaldo;
  • Cairns, Nigel J;
  • McQuillin, Andrew;
  • Cao, Chuanhai;
  • Livingston, Gill;
  • Carlson, Chris S;
  • Bass, Nicholas J;
  • Carlsson, Cynthia M;
  • Hardy, John;
  • Carney, Regina M;
  • Bras, Jose;
  • Carrasquillo, Minerva M;
  • Guerreiro, Rita;
  • Allen, Mariet;
  • Chui, Helena C;
  • Fisher, Elizabeth;
  • Masullo, Carlo;
  • Crocco, Elizabeth A;
  • DeCarli, Charles;
  • Bisceglio, Gina;
  • Dick, Malcolm;
  • Ma, Li;
  • Duara, Ranjan;
  • Graff-Radford, Neill R;
  • Evans, Denis A;
  • Hodges, Angela;
  • Faber, Kelley M;
  • Scherer, Martin;
  • Fallon, Kenneth B;
  • Riemenschneider, Matthias;
  • Fardo, David W;
  • Heun, Reinhard;
  • Farlow, Martin R;
  • Kölsch, Heike;
  • Ferris, Steven;
  • Leber, Markus;
  • Foroud, Tatiana M;
  • Heuser, Isabella;
  • Galasko, Douglas R;
  • Giegling, Ina;
  • Gearing, Marla;
  • Hüll, Michael;
  • Geschwind, Daniel H;
  • Gilbert, John R;
  • Morris, John;
  • Green, Robert C;
  • Mayo, Kevin;
  • Growdon, John H;
  • Feulner, Thomas;
  • Hamilton, Ronald L;
  • Harrell, Lindy E;
  • Drichel, Dmitriy;
  • Honig, Lawrence S;
  • Cushion, Thomas D;
  • Huentelman, Matthew J;
  • Hollingworth, Paul;
  • Hulette, Christine M;
  • Hyman, Bradley T;
  • Marshall, Rachel;
  • Jarvik, Gail P;
  • Meggy, Alun;
  • Abner, Erin;
  • Menzies, Georgina E;
  • Jin, Lee-Way;
  • Leonenko, Ganna;
  • Real, Luis M;
  • Jun, Gyungah R;
  • Baldwin, Clinton T;
  • Grozeva, Detelina;
  • Karydas, Anna;
  • Russo, Giancarlo;
  • Kaye, Jeffrey A;
  • Kim, Ronald;
  • Jessen, Frank;
  • Kowall, Neil W;
  • Vellas, Bruno;
  • Kramer, Joel H;
  • Vardy, Emma;
  • LaFerla, Frank M;
  • Jöckel, Karl-Heinz;
  • Lah, James J;
  • Dichgans, Martin;
  • Leverenz, James B;
  • Mann, David;
  • Levey, Allan I;
  • Pickering-Brown, Stuart;
  • Lieberman, Andrew P;
  • Klopp, Norman;
  • Lunetta, Kathryn L;
  • Wichmann, H-Erich;
  • Lyketsos, Constantine G;
  • Morgan, Kevin;
  • Marson, Daniel C;
  • Brown, Kristelle;
  • Martiniuk, Frank;
  • Medway, Christopher;
  • Mash, Deborah C;
  • Nöthen, Markus M;
  • Masliah, Eliezer;
  • Hooper, Nigel M;
  • McCormick, Wayne C;
  • Daniele, Antonio;
  • McCurry, Susan M;
  • Bayer, Anthony;
  • McDavid, Andrew N;
  • Gallacher, John;
  • McKee, Ann C;
  • van den Bussche, Hendrik;
  • Mesulam, Marsel;
  • Brayne, Carol;
  • Miller, Bruce L;
  • Riedel-Heller, Steffi;
  • Miller, Carol A;
  • Miller, Joshua W;
  • Al-Chalabi, Ammar;
  • Morris, John C;
  • Shaw, Christopher E;
  • Myers, Amanda J;
  • Wiltfang, Jens;
  • O'Bryant, Sid;
  • Olichney, John M;
  • Alvarez, Victoria;
  • Parisi, Joseph E;
  • Singleton, Andrew B;
  • Paulson, Henry L;
  • Collinge, John;
  • Perry, William R;
  • Mead, Simon;
  • Peskind, Elaine;
  • Cribbs, David H;
  • Rossor, Martin;
  • Pierce, Aimee;
  • Ryan, Natalie S;
  • Poon, Wayne W;
  • Nacmias, Benedetta;
  • Potter, Huntington;
  • Sorbi, Sandro;
  • Quinn, Joseph F;
  • Sacchinelli, Eleonora;
  • Raj, Ashok;
  • Spalletta, Gianfranco;
  • Raskind, Murray;
  • Caltagirone, Carlo;
  • Bossù, Paola;
  • Orfei, Maria Donata;
  • Reisberg, Barry;
  • Clarke, Robert;
  • Reitz, Christiane;
  • Smith, A David;
  • Ringman, John M;
  • Warden, Donald;
  • Roberson, Erik D;
  • Wilcock, Gordon;
  • Rogaeva, Ekaterina;
  • Bruni, Amalia Cecilia;
  • Rosen, Howard J;
  • Gallo, Maura;
  • Rosenberg, Roger N;
  • Ben-Shlomo, Yoav;
  • Sager, Mark A;
  • Mecocci, Patrizia;
  • Saykin, Andrew J;
  • Pastor, Pau;
  • Cuccaro, Michael L;
  • Vance, Jeffery M;
  • Schneider, Julie A;
  • Schneider, Lori S;
  • Slifer, Susan;
  • Seeley, William W;
  • Smith, Amanda G;
  • Sonnen, Joshua A;
  • Spina, Salvatore;
  • Stern, Robert A;
  • Swerdlow, Russell H;
  • Tang, Mitchell;
  • Tanzi, Rudolph E;
  • 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;
  • Saba, Yasaman;
  • Pilotto, Alberto;
  • Bullido, Maria J;
  • Peters, Oliver;
  • Crane, Paul K;
  • Bennett, David;
  • Bosco, Paola;
  • Coto, Eliecer;
  • Boccardi, Virginia;
  • De Jager, Phil L;
  • Lleo, Alberto;
  • Warner, Nick;
  • Lopez, Oscar L;
  • Ingelsson, Martin;
  • Deloukas, Panagiotis;
  • Cruchaga, Carlos;
  • Graff, Caroline;
  • Gwilliam, Rhian;
  • Fornage, Myriam;
  • Goate, Alison M;
  • Sanchez-Juan, Pascual;
  • Kehoe, Patrick G;
  • Amin, Najaf;
  • Ertekin-Taner, Nilifur;
  • Berr, Claudine;
  • Debette, Stéphanie;
  • Love, Seth;
  • Launer, Lenore J;
  • Younkin, Steven G;
  • Dartigues, Jean-Francois;
  • Corcoran, Chris;
  • Ikram, M Arfan;
  • Dickson, Dennis W;
  • Nicolas, Gael;
  • Campion, Dominique;
  • Tschanz, JoAnn;
  • Schmidt, Helena;
  • Hakonarson, Hakon;
  • Clarimon, Jordi;
  • Munger, Ron;
  • Schmidt, Reinhold;
  • Farrer, Lindsay A;
  • Van Broeckhoven, Christine;
  • C O'Donovan, Michael;
  • DeStefano, Anita L;
  • Jones, Lesley;
  • Haines, Jonathan L;
  • Deleuze, Jean-Francois;
  • Owen, Michael J;
  • Gudnason, Vilmundur;
  • Mayeux, Richard;
  • Escott-Price, Valentina;
  • Psaty, Bruce M;
  • Ramirez, Alfredo;
  • Wang, Li-San;
  • Ruiz, Agustin;
  • van Duijn, Cornelia M;
  • Holmans, Peter A;
  • Seshadri, Sudha;
  • Williams, Julie;
  • Amouyel, Phillippe;
  • Schellenberg, Gerard D;
  • Lambert, Jean-Charles;
  • Pericak-Vance, Margaret A;
  • Alzheimer Disease Genetics Consortium (ADGC),;
  • European Alzheimer’s Disease Initiative (EADI),;
  • Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE),;
  • Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES),
  • et al.
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

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