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

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 f...

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Autores: Kunkle, BW; Grenier-Boley, B; Sims, R; Bis, JC; Damotte, V; Naj, AC; Boland, A; Vronskaya, M; van der Lee, SJ; Amlie-Wolf, A; Bellenguez, C; Frizatti, A; Chouraki, V; Martin, ER; Sleegers, K; Badarinarayan, N; Jakobsdottir, J; Hamilton-Nelson, KL; Moreno-Grau, S; Olaso, R; Raybould, R; Chen, YN; Kuzma, AB; Hiltunen, M; Morgan, T; Ahmad, S; Vardarajan, BN; Epelbaum, J; Hoffmann, P; Boada, M; Beecham, GW; Garnier, JG; Harold, D; Fitzpatrick, AL; Valladares, O; Moutet, ML; Gerrish, A; Smith, AV; Qu, LM; Bacq, D; Denning, N; Jian, XQ; Zhao, Y; Del Zompo, M; Fox, NC; Choi, SH; Mateo, I; Hughes, JT; Adams, HH; Malamon, J; Sanchez-Garcia, F; Patel, Y; Brody, JA; Dombroski, BA; Naranjo, MCD; Daniilidou, M; Eiriksdottir, G; Mukherjee, S; Wallon, D; Uphill, J; Aspelund, T; Cantwell, LB; Garzia, F; Galimberti, D; Hofer, E; Butkiewicz, M; Fin, B; Scarpini, E; Sarnowski, C; Bush, WS; Meslage, S; Kornhuber, J; White, CC; Song, Y; Barber, RC; Engelborghs, S; Sordon, S; Voijnovic, D; Adams, PM; Vandenberghe, R; Mayhaus, M; Cupples, LA; Albert, MS; De Deyn, PP; Gu, W; Himali, JJ; Beekly, D; Squassina, A; Hartmann, AM; Orellana, A; Blacker, D; Rodriguez-Rodriguez, E; Lovestone, S; Garcia, ME; Doody, RS; Munoz-Fernadez, C; Sussams, R; Lin, HH; Fairchild, TJ; Benito, YA; Holmes, C; Karamujic-Comic, H; Frosch, MP; Thonberg, H; Maier, W; Roschupkin, G; Ghetti, B; Giedraitis, V; Kawalia, A; Li, S; Huebinger, RM; Kilander, L; Moebus, S; Hernandez, I; Kamboh, MI; Brundin, R; Turton, J; Yang, Q; Katz, MJ; Concari, L; Lord, J; Beiser, AS; Keene, CD; Helisalmi, S; Kloszewska, I; Kukull, WA; Koivisto, AM; Lynch, A; Tarraga, L; Larson, EB; Haapasalo, A; Lawlor, B; Mosley, TH; Lipton, RB; Solfrizzi, V; Gill, M; Longstreth, WT; Montine, TJ; Frisardi, V; Diez-Fairen, M; Rivadeneira, F; Petersen, RC; Deramecourt, V; Alvarez, I; Salani, F; Ciaramella, A; Boerwinkle, E; Reiman, EM; Fievet, N; Rotter, JI; Reisch, JS; Hanon, O; Cupidi, C; Uitterlinden, AGA; Royall, DR; Dufouil, C; Maletta, RG; de Rojas, I; Sano, M; Brice, A; Cecchetti, R; St George-Hyslop, P; Ritchie, K; Tsolaki, M; Tsuang, DW; Dubois, B; Craig, D; Wu, CK; Soininen, H; Avramidou, D; Albin, RL; Fratiglioni, L; Germanou, A; Apostolova, LG; Keller, L; Koutroumani, M; Arnold, SE; Panza, F; Gkatzima, O; Asthana, S; Hannequin, D; Whitehead, P; Atwood, CS; Caffarra, P; Hampel, H; Quintela, I; Carracedo, A; Lannfelt, L; Rubinsztein, DC; Barnes, LL; Pasquier, F; Frolich, L; Barral, S; McGuinness, B; Beach, TG; Johnston, JA; Becker, JT; Passmore, P; Bigio, EH; Schott, JM; Bird, TD; Warren, JD; Boeve, BF; Lupton, MK; Bowen, JD; Proitsi, P; Boxer, A; Powell, JF; Burke, JR; Kauwe, JSK; Burns, JM; Mancuso, M; Buxbaum, JD; Bonuccelli, U; Cairns, NJ; McQuillin, A; Cao, CH; Livingston, G; Carlson, CS; Bass, NJ; Carlsson, CM; Hardy, J; Carney, RM; Bras, J; Carrasquillo, MM; Guerreiro, R; Allen, M; Chui, HC; Fisher, E; Masullo, C; Crocco, EA; DeCarli, C; Bisceglio, G; Dick, M; Ma, L; Duara, R; Graff-Radford, NR; Evans, DA; Hodges, A; Faber, KM; Scherer, M; Fallon, KB; Riemenschneider, M; Fardo, DW; Heun, R; Farlow, MR; Kolsch, H; Ferris, S; Leber, M; Foroud, TM; Heuser, I; Galasko, DR; Giegling, I; Gearing, M; Hull, M; Geschwind, DH; Gilbert, JR; Morris, J; Green, RC; Mayo, K; Growdon, JH; Feulner, T; Hamilton, RL; Harrell, LE; Drichel, D; Honig, LS; Cushion, TD; Huentelman, MJ; Hollingworth, P; Hulette, CM; Hyman, BT; Marshall, R; Jarvik, GP; Meggy, A; Abner, E; Menzies, GE; Jin, LW; Leonenko, G; Real, LM; Jun, GR; Baldwin, CT; Grozeva, D; Karydas, A; Russo, G; Kaye, JA; Kim, R; Jessen, F; Kowall, NW; Vellas, B; Kramer, JH; Vardy, E; LaFerla, FM; Jockel, KH; Lah, JJ; Dichgans, M; Leverenz, JB; Mann, D; Levey, AI; Pickering-Brown, S; Lieberman, AP; Klopp, N; Lunetta, KL; Wichmann, HE; Lyketsos, CG; Morgan, K; Marson, DC; Brown, K; Martiniuk, F; Medway, C; Mash, DC; Nothen, MM; Masliah, E; Hooper, NM; McCormick, WC; Daniele, A; McCurry, SM; Bayer, A; McDavid, AN; Gallacher, J; McKee, AC; van den Bussche, H; Mesulam, M; Brayne, C; Miller, BL; Riedel-Heller, S; Miller, CA; Miller, JW; Al-Chalabi, A; Morris, JC; Shaw, CE; Myers, AJ; Wiltfang, J; O'Bryant, S; Olichney, JM; Alvarez, V; Parisi, JE; Singleton, AB; Paulson, HL; Collinge, J; Perry, WR; Mead, S; Peskind, E; Cribbs, DH; Rossor, M; Pierce, A; Ryan, NS; Poon, WW; Nacmias, B; Potter, H; Sorbi, S; Quinn, JF; Sacchinelli, E; Raj, A; Spalletta, G; Raskind, M; Caltagirone, C; Bossu, P; Orfei, MD; Reisberg, B; Clarke, R; Reitz, C; Smith, AD; Ringman, JM; Warden, D; Roberson, ED; Wilcock, G; Rogaeva, E; Bruni, AC; Rosen, HJ; Gallo, M; Rosenberg, RN; Ben-Shlomo, Y; Sager, MA; Mecocci, P; Saykin, AJ; Pastor, P; Cuccaro, ML; Vance, JM; Schneider, JA; Schneider, LS; Slifer, S; Seeley, WW; Smith, AG; Sonnen, JA; Spina, S; Stern, RA; Swerdlow, RH; Tang, M; Tanzi, RE; Trojanowski, JQ; Troncoso, JC; Van Deerlin, VM; Van Eldik, LJ; Vinters, HV; Vonsattel, JP; Weintraub, S; Welsh-Bohmer, KA; Wilhelmsen, KC; Williamson, J; Wingo, TS; Woltjer, RL; Wright, CB; Yu, CE; Yu, L; Saba, Y; Pilotto, A; Bullido, MJ; Peters, O; Crane, PK; Bennett, D; Bosco, P; Coto, E; Boccardi, V; De Jager, PL; Lleo, A; Warner, N; Lopez, OL; Ingelsson, M; Deloukas, P; Cruchaga, C; Graff, C; Gwilliam, R; Fornage, M; Goate, AM; Sanchez-Juan, P; Kehoe, PG; Amin, N; Ertekin-Taner, N; Berr, C; Debette, S; Love, S; Launer, LJ; Younkin, SG; Dartigues, JF; Corcoran, C; Ikram, MA; Dickson, DW; Nicolas, G; Campion, D; Tschanz, J; Schmidt, H; Hakonarson, H; Clarimon, J; Munger, R; Schmidt, R; Farrer, LA; Van Broeckhoven, C; O'Donovan, MC; DeStefano, AL; Jones, L; Haines, JL; Deleuze, JF; Owen, MJ; Gudnason, V; Mayeux, R; Escott-Price, V; Psaty, BM; Ramirez, A; Wang, LS; Ruiz, A; van Duijn, CM; Holmans, PA; Seshadri, S; Williams, J; Amouyel, P; Schellenberg, GD; Lambert, JC; Pericak-Vance, MA
Tipo de documento: Artículo
Estado:Published version
Fecha de publicación:2019
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p2946
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2946
https://europepmc.org/articles/pmc6463297
Nivel de acceso:Acceso abierto
Sumario: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 A beta 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 x 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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