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Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

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

Posted 04 Apr 2018
bioRxiv DOI: 10.1101/294629

Late-onset Alzheimers disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly, and risk is partially driven by genetics. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS). To identify additional LOAD risk loci, we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Abeta processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7) indicating that additional rare variants remain to be identified.

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