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

Kunkle, B.W.; Grenier-Boley, B.; Sims, R.; Bis, J.C.; Damotte, V.; Naj, A.C.; Boland, A.; Vronskaya, M.; van der Lee, S.J.; Amlie-Wolf, A.; Bellenguez, C.; Frizatti, A.; Chouraki, V.; Martin, E.R.; Sleegers, K.; Badarinarayan, N.; Jakobsdottir, J.; Hamilton-Nelson, K.L.; Moreno-Grau, S.; Olaso, R.; Raybould, R.; Chen, Y.; Kuzma, A.B.; Hiltunen, M.; Morgan, T.; Ahmad, S.; Vardarajan, B.N.; Epelbaum, J.; Hoffmann, P.; Boada, M.; Beecham, G.W.; Garnier, J.; Harold, D.; Fitzpatrick, A.L.; Valladares, O.; Moutet, M.; Gerrish, A.; Smith, A.V.; Liming, Q.; Bacq, D.; Denning, N.; Jian, X.; Zhao, Y.; Del Zompo, M.; Fox, N.C.; Choi, S.; Mateo, I.; Hughes, J.T.; Adams, H.H.; Malamon, J.; Sanchez-Garcia, F.; Patel, Y.; Brody, J.A.; Dombroski, B.A.; Naranjo, M.C.D.; Daniilidou, M.; Eiriksdottir, G.; Mukherjee, S.; Wallon, D.; Uphill, J.; Aspelund, T.; Cantwell, L.B.; Garzia, F.; Galimberti, D.; Hofer, E.; Butkiewicz, M.; Fin, B.; Scarpini, E.; Sarnowski, C.; Bush, W.S.; Meslage, S.; Kornhuber, J.; White, C.C.; Song, Y.; Barber, R.C.; Engelborghs, S.; Sordon, S.; Voijnovic, D.; Adams, P.M.; Vandenberghe, R.; Mayhaus, M.; Cupples, L.A.; Albert, M.S.; De Deyn, P.P.; Wei, G.; Himali, J.J.; Beekly, D.; Squassina, A.; Hartmann, A.M.; Orellana, A.; Blacker, D.; Rodriguez-Rodriguez, E.; Lovestone, S.; Garcia, M.E.; Doody, R.S.; Munoz-Fernadez, C.; Sussams, R.; Lin, H.; Fairchild, T.J.; Benito, Y.A.; Holmes, C.; Karamujić-Čomić, H.; Frosch, M.P.; Thonberg, H.; Maier, W.; Roschupkin, G.; Ghetti, B.; Giedraitis, V.; Kawalia, A.; Shuo, L.; Huebinger, R.M.; Kilander, L.; Moebus, S.; Hernández, I.; Kamboh, M.I.; Brundin, R.; Turton, J.; Yang, Q.; Katz, M.J.; Concari, L.; Lord, J.; Beiser, A.S.; Keene, C.D.; Helisalmi, S.; Kloszewska, I.; Kukull, W.A.; Koivisto, A.M.; Lynch, A.; Tarraga, L.; Larson, E.B.; Haapasalo, A.; Lawlor, B.; Mosley, T.H.; Lipton, R.B.; Solfrizzi, V.; Gill, M.; Longstreth, W.T.; Montine, T.J.; Frisardi, V.; Diez-Fairen, M.; Rivadeneira, F.; Petersen, R.C.; Deramecourt, V.; Alvarez, I.; Salani, F.; Ciaramella, A.; Boerwinkle, E.; Reiman, E.M.; Fievet, N.; Rotter, J.I.; Reisch, J.S.; Hanon, O.; Cupidi, C.; Andre Uitterlinden, A.G.; Royall, D.R.; Dufouil, C.; Maletta, R.G.; de Rojas, I.; Sano, M.; Brice, A.; Cecchetti, R.; George-Hyslop, P.S.; Ritchie, K.; Tsolaki, M.; Tsuang, D.W.; Dubois, B.; Craig, D.; Chuang-Kuo, W.; Soininen, H.; Avramidou, D.; Albin, R.L.; Fratiglioni, L.; Germanou, A.; Apostolova, L.G.; Keller, L.; Koutroumani, M.; Arnold, S.E.; Panza, F.; Gkatzima, O.; Asthana, S.; Hannequin, D.; Whitehead, P.; Atwood, C.S.; Caffarra, P.; Hampel, H.; Quintela, I.; Carracedo, Á.; Lannfelt, L.; Rubinsztein, D.C.; Barnes, L.L.; Pasquier, F.; Frölich, L.; Barral, S.; Mcguinness, B.; Beach, T.G.; Johnston, J.A.; Becker, J.T.; Passmore, P.; Bigio, E.H.; Schott, J.M.; Bird, T.D.; Warren, J.D.; Boeve, B.F.; Lupton, M.K.; Bowen, J.D.; Proitsi, P.; Boxer, A.; Powell, J.F.; Burke, J.R.; Kauwe, J.S.K.; Burns, J.M.; Mancuso, M.; Buxbaum, J.D.; Bonuccelli, U.; Cairns, N.J.; Mcquillin, A.; Cao, C.; Livingston, G.; Carlson, C.S.; Bass, N.J.; Carlsson, C.M.; Hardy, J.; Carney, R.M.; Bras, J.; Carrasquillo, M.M.; Guerreiro, R.; Allen, M.; Chui, H.C.; Fisher, E.; Masullo, C.; Crocco, E.A.; Decarli, C.; Bisceglio, G.; Dick, M.; Li, M.; Duara, R.; Graff-Radford, N.R.; Evans, D.A.; Hodges, A.; Faber, K.M.; Scherer, M.; Fallon, K.B.; Riemenschneider, M.; Fardo, D.W.; Heun, R.; Farlow, M.R.; Kölsch, H.; Ferris, S.; Leber, M.; Foroud, T.M.; Heuser, I.; Galasko, D.R.; Giegling, I.; Gearing, M.; Hüll, M.; Geschwind, D.H.; Gilbert, J.R.; Morris, J.; Green, R.C.; Mayo, K.; Growdon, J.H.; Feulner, T.; Hamilton, R.L.; Harrell, L.E.; Drichel, D.; Honig, L.S.; Cushion, T.D.; Huentelman, M.J.; Hollingworth, P.; Hulette, C.M.; Hyman, B.T.; Marshall, R.; Jarvik, G.P.; Meggy, A.; Abner, E.; Menzies, G.E.; Jin, L.; Leonenko, G.; Real, L.M.; Jun, G.R.; Baldwin, C.T.; Grozeva, D.; Karydas, A.; Russo, G.; Kaye, J.A.; Kim, R.; Jessen, F.; Kowall, N.W.; Vellas, B.; Kramer, J.H.; Vardy, E.; Laferla, F.M.; Jöckel, K.; Lah, J.J.; Dichgans, M.; Leverenz, J.B.; Mann, D.; Levey, A.I.; Pickering-Brown, S.; Lieberman, A.P.; Klopp, N.; Lunetta, K.L.; Wichmann, H.; Lyketsos, C.G.; Morgan, K.; Marson, D.C.; Brown, K.; Martiniuk, F.; Medway, C.; Mash, D.C.; Nöthen, M.M.; Masliah, E.; Hooper, N.M.; Mccormick, W.C.; Daniele, A.; Mccurry, S.M.; Bayer, A.; Mcdavid, A.N.; Gallacher, J.; Mckee, A.C.; van den Bussche, H.; Mesulam, M.; Brayne, C.; Miller, B.L.; Riedel-Heller, S.; Miller, C.A.; Miller, J.W.; Al-Chalabi, A.; Morris, J.C.; Shaw, C.E.; Myers, A.J.; Wiltfang, J.; O'Bryant, S.; Olichney, J.M.; Alvarez, V.; Parisi, J.E.; Singleton, A.B.; Paulson, H.L.; Collinge, J.; Perry, W.R.; Mead, S.; Peskind, E.; Cribbs, D.H.; Rossor, M.; Pierce, A.; Ryan, N.S.; Poon, W.W.; Nacmias, B.; Potter, H.; Sorbi, S.; Quinn, J.F.; Sacchinelli, E.; Raj, A.; Spalletta, G.; Raskind, M.; Caltagirone, C.; Bossù, P.; Orfei, M.D.; Reisberg, B.; Clarke, R.; Reitz, C.; Smith, A.D.; Ringman, J.M.; Warden, D.; Roberson, E.D.; Wilcock, G.; Rogaeva, E.; Bruni, A.C.; Rosen, H.J.; Gallo, M.; Rosenberg, R.N.; Ben-Shlomo, Y.; Sager, M.A.; Mecocci, P.; Saykin, A.J.; Pastor, P.; Cuccaro, M.L.; Vance, J.M.; Schneider, J.A.; Schneider, L.S.; Slifer, S.; Seeley, W.W.; Smith, A.G.; Sonnen, J.A.; Spina, S.; Stern, R.A.; Swerdlow, R.H.; Tang, M.; Tanzi, R.E.; Trojanowski, J.Q.; Troncoso, J.C.; Van Deerlin, V.M.; Van Eldik, L.J.; Vinters, H.V.; Vonsattel, J.P.; Weintraub, S.; Welsh-Bohmer, K.A.; Wilhelmsen, K.C.; Williamson, J.; Wingo, T.S.; Woltjer, R.L.; Wright, C.B.; Chang-En, Y.; Lei, Y.; Saba, Y.; Pilotto, A.; Bullido, M.J.; Peters, O.; Crane, P.K.; Bennett, D.; Bosco, P.; Coto, E.; Boccardi, V.; De Jager, P.L.; Lleo, A.; Warner, N.; Lopez, O.L.; Ingelsson, M.; Deloukas, P.; Cruchaga, C.; Graff, C.; Gwilliam, R.; Fornage, M.; Goate, A.M.; Sanchez-Juan, P.; Kehoe, P.G.; Amin, N.; Ertekin-Taner, N.; Berr, C.; Debette, S.; Love, S.; Launer, L.J.; Younkin, S.G.; Dartigues, J.; Corcoran, C.; Ikram, M.A.; Dickson, D.W.; Nicolas, G.; Campion, D.; Tschanz, J.; Schmidt, H.; Hakonarson, H.; Clarimon, J.; Munger, R.; Schmidt, R.; Farrer, L.A.; Van Broeckhoven, C.; C O'Donovan, M.; Destefano, A.L.; Jones, L.; Haines, J.L.; Deleuze, J.; Owen, M.J.; Gudnason, V.; Mayeux, R.; Escott-Price, V.; Psaty, B.M.; Ramirez, A.; Wang, L.; Ruiz, A.; van Duijn, C.M.; Holmans, P.A.; Seshadri, S.; Williams, J.; Amouyel, P.; Schellenberg, G.D.; Lambert, J.; Pericak-Vance, M.A.

doi:10.1038/s41588-019-0358-2

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.

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing / B.W. Kunkle, B. Grenier-Boley, R. Sims, J.C. Bis, V. Damotte, A.C. Naj, A. Boland, M. Vronskaya, S.J. van der Lee, A. Amlie-Wolf, C. Bellenguez, A. Frizatti, V. Chouraki, E.R. Martin, K. Sleegers, N. Badarinarayan, J. Jakobsdottir, K.L. Hamilton-Nelson, S. Moreno-Grau, R. Olaso, R. Raybould, Y. Chen, A.B. Kuzma, M. Hiltunen, T. Morgan, S. Ahmad, B.N. Vardarajan, J. Epelbaum, P. Hoffmann, M. Boada, G.W. Beecham, J. Garnier, D. Harold, A.L. Fitzpatrick, O. Valladares, M. Moutet, A. Gerrish, A.V. Smith, L. Qu, D. Bacq, N. Denning, X. Jian, Y. Zhao, M. Del Zompo, N.C. Fox, S. Choi, I. Mateo, J.T. Hughes, H.H. Adams, J. Malamon, F. Sanchez-Garcia, Y. Patel, J.A. Brody, B.A. Dombroski, M.C.D. Naranjo, M. Daniilidou, G. Eiriksdottir, S. Mukherjee, D. Wallon, J. Uphill, T. Aspelund, L.B. Cantwell, F. Garzia, D. Galimberti, E. Hofer, M. Butkiewicz, B. Fin, E. Scarpini, C. Sarnowski, W.S. Bush, S. Meslage, J. Kornhuber, C.C. White, Y. Song, R.C. Barber, S. Engelborghs, S. Sordon, D. Voijnovic, P.M. Adams, R. Vandenberghe, M. Mayhaus, L.A. Cupples, M.S. Albert, P.P. De Deyn, W. Gu, J.J. Himali, D. Beekly, A. Squassina, A.M. Hartmann, A. Orellana, D. Blacker, E. Rodriguez-Rodriguez, S. Lovestone, M.E. Garcia, R.S. Doody, C. Munoz-Fernadez, R. Sussams, H. Lin, T.J. Fairchild, Y.A. Benito, C. Holmes, H. Karamujić-Čomić, M.P. Frosch, H. Thonberg, W. Maier, G. Roschupkin, B. Ghetti, V. Giedraitis, A. Kawalia, S. Li, R.M. Huebinger, L. Kilander, S. Moebus, I. Hernández, M.I. Kamboh, R. Brundin, J. Turton, Q. Yang, M.J. Katz, L. Concari, J. Lord, A.S. Beiser, C.D. Keene, S. Helisalmi, I. Kloszewska, W.A. Kukull, A.M. Koivisto, A. Lynch, L. Tarraga, E.B. Larson, A. Haapasalo, B. Lawlor, T.H. Mosley, R.B. Lipton, V. Solfrizzi, M. Gill, W.T. Longstreth, T.J. Montine, V. Frisardi, M. Diez-Fairen, F. Rivadeneira, R.C. Petersen, V. Deramecourt, I. Alvarez, F. Salani, A. Ciaramella, E. Boerwinkle, E.M. Reiman, N. Fievet, J.I. Rotter, J.S. Reisch, O. Hanon, C. Cupidi, A.G. Andre Uitterlinden, D.R. Royall, C. Dufouil, R.G. Maletta, I. de Rojas, M. Sano, A. Brice, R. Cecchetti, P.S. George-Hyslop, K. Ritchie, M. Tsolaki, D.W. Tsuang, B. Dubois, D. Craig, C. Wu, H. Soininen, D. Avramidou, R.L. Albin, L. Fratiglioni, A. Germanou, L.G. Apostolova, L. Keller, M. Koutroumani, S.E. Arnold, F. Panza, O. Gkatzima, S. Asthana, D. Hannequin, P. Whitehead, C.S. Atwood, P. Caffarra, H. Hampel, I. Quintela, Á. Carracedo, L. Lannfelt, D.C. Rubinsztein, L.L. Barnes, F. Pasquier, L. Frölich, S. Barral, B. McGuinness, T.G. Beach, J.A. Johnston, J.T. Becker, P. Passmore, E.H. Bigio, J.M. Schott, T.D. Bird, J.D. Warren, B.F. Boeve, M.K. Lupton, J.D. Bowen, P. Proitsi, A. Boxer, J.F. Powell, J.R. Burke, J.S.K. Kauwe, J.M. Burns, M. Mancuso, J.D. Buxbaum, U. Bonuccelli, N.J. Cairns, A. McQuillin, C. Cao, G. Livingston, C.S. Carlson, N.J. Bass, C.M. Carlsson, J. Hardy, R.M. Carney, J. Bras, M.M. Carrasquillo, R. Guerreiro, M. Allen, H.C. Chui, E. Fisher, C. Masullo, E.A. Crocco, C. DeCarli, G. Bisceglio, M. Dick, L. Ma, R. Duara, N.R. Graff-Radford, D.A. Evans, A. Hodges, K.M. Faber, M. Scherer, K.B. Fallon, M. Riemenschneider, D.W. Fardo, R. Heun, M.R. Farlow, H. Kölsch, S. Ferris, M. Leber, T.M. Foroud, I. Heuser, D.R. Galasko, I. Giegling, M. Gearing, M. Hüll, D.H. Geschwind, J.R. Gilbert, J. Morris, R.C. Green, K. Mayo, J.H. Growdon, T. Feulner, R.L. Hamilton, L.E. Harrell, D. Drichel, L.S. Honig, T.D. Cushion, M.J. Huentelman, P. Hollingworth, C.M. Hulette, B.T. Hyman, R. Marshall, G.P. Jarvik, A. Meggy, E. Abner, G.E. Menzies, L. Jin, G. Leonenko, L.M. Real, G.R. Jun, C.T. Baldwin, D. Grozeva, A. Karydas, G. Russo, J.A. Kaye, R. Kim, F. Jessen, N.W. Kowall, B. Vellas, J.H. Kramer, E. Vardy, F.M. LaFerla, K. Jöckel, J.J. Lah, M. Dichgans, J.B. Leverenz, D. Mann, A.I. Levey, S. Pickering-Brown, A.P. Lieberman, N. Klopp, K.L. Lunetta, H. Wichmann, C.G. Lyketsos, K. Morgan, D.C. Marson, K. Brown, F. Martiniuk, C. Medway, D.C. Mash, M.M. Nöthen, E. Masliah, N.M. Hooper, W.C. McCormick, A. Daniele, S.M. McCurry, A. Bayer, A.N. McDavid, J. Gallacher, A.C. McKee, H. van den Bussche, M. Mesulam, C. Brayne, B.L. Miller, S. Riedel-Heller, C.A. Miller, J.W. Miller, A. Al-Chalabi, J.C. Morris, C.E. Shaw, A.J. Myers, J. Wiltfang, S. O'Bryant, J.M. Olichney, V. Alvarez, J.E. Parisi, A.B. Singleton, H.L. Paulson, J. Collinge, W.R. Perry, S. Mead, E. Peskind, D.H. Cribbs, M. Rossor, A. Pierce, N.S. Ryan, W.W. Poon, B. Nacmias, H. Potter, S. Sorbi, J.F. Quinn, E. Sacchinelli, A. Raj, G. Spalletta, M. Raskind, C. Caltagirone, P. Bossù, M.D. Orfei, B. Reisberg, R. Clarke, C. Reitz, A.D. Smith, J.M. Ringman, D. Warden, E.D. Roberson, G. Wilcock, E. Rogaeva, A.C. Bruni, H.J. Rosen, M. Gallo, R.N. Rosenberg, Y. Ben-Shlomo, M.A. Sager, P. Mecocci, A.J. Saykin, P. Pastor, M.L. Cuccaro, J.M. Vance, J.A. Schneider, L.S. Schneider, S. Slifer, W.W. Seeley, A.G. Smith, J.A. Sonnen, S. Spina, R.A. Stern, R.H. Swerdlow, M. Tang, R.E. Tanzi, J.Q. Trojanowski, J.C. Troncoso, V.M. Van Deerlin, L.J. Van Eldik, H.V. Vinters, J.P. Vonsattel, S. Weintraub, K.A. Welsh-Bohmer, K.C. Wilhelmsen, J. Williamson, T.S. Wingo, R.L. Woltjer, C.B. Wright, C. Yu, L. Yu, Y. Saba, A. Pilotto, M.J. Bullido, O. Peters, P.K. Crane, D. Bennett, P. Bosco, E. Coto, V. Boccardi, P.L. De Jager, A. Lleo, N. Warner, O.L. Lopez, M. Ingelsson, P. Deloukas, C. Cruchaga, C. Graff, R. Gwilliam, M. Fornage, A.M. Goate, P. Sanchez-Juan, P.G. Kehoe, N. Amin, N. Ertekin-Taner, C. Berr, S. Debette, S. Love, L.J. Launer, S.G. Younkin, J. Dartigues, C. Corcoran, M.A. Ikram, D.W. Dickson, G. Nicolas, D. Campion, J. Tschanz, H. Schmidt, H. Hakonarson, J. Clarimon, R. Munger, R. Schmidt, L.A. Farrer, C. Van Broeckhoven, M. C O'Donovan, A.L. DeStefano, L. Jones, J.L. Haines, J. Deleuze, M.J. Owen, V. Gudnason, R. Mayeux, V. Escott-Price, B.M. Psaty, A. Ramirez, L. Wang, A. Ruiz, C.M. van Duijn, P.A. Holmans, S. Seshadri, J. Williams, P. Amouyel, G.D. Schellenberg, J. Lambert, M.A. Pericak-Vance. - In: NATURE GENETICS. - ISSN 1061-4036. - 51:3(2019 Mar), pp. 414-430. [10.1038/s41588-019-0358-2]

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

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;D. Galimberti;Hofer, Edith;Butkiewicz, Mariusz;Fin, Bertrand;E. Scarpini;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;Roschupkin, Gena;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, W T;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, A G;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 S K;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, 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2019

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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	Settori scientifico-disciplinari dell'articolo
	
			Settore BIO/13 - Biologia Applicata
Settore MED/26 - Neurologia
		
	Data di pubblicazione
	
			mar-2019
		
	Rivista in ANCE
	
			NATURE GENETICS
		
	DOI
	
			https://dx.doi.org/10.1038/s41588-019-0358-2
		
	Tipologia
	
			Article (author)
		
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			01 - Articolo su periodico

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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/634163

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