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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing
- Source :
- NATURE GENETICS, r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau, instname, Nature Genetics, 51(3), 414-+. Nature Publishing Group, 2019, ' Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing ', Nature Genetics, vol. 51, no. 3, pp. 414-430 . https://doi.org/10.1038/s41588-019-0358-2, Nature Genetics, 51(3), 414-430. Nature Publishing Group, 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 G, Harold, D, Fitzpatrick, A L, Valladares, O, Moutet, M L, Gerrish, A, Smith, A V, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Del Zompo, M, Fox, N C, Choi, S H, 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, Gu, W, 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, Li, S, Huebinger, R M, Kilander, L, Moebus, S, Hernández, I, Kamboh, M I, Brundin, R M, 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, Wu, C K, 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, Ma, L, 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 C, 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 W, 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 H, 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 E, 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 G, 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, Yu, C E, Yu, L, 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 F, Corcoran, C, Ikram, M A, Dickson, D W, Nicolas, G, Campion, D, Tschanz, J A, 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 F, Owen, M J, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, B M, Ramirez, A, Wang, L S, Ruiz, A, van Duijn, C M, Holmans, P A, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, G D, Lambert, J C & Pericak-Vance, M A 2019, ' Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing ', Nature Genetics, vol. 51, no. 3, pp. 414-430 . https://doi.org/10.1038/s41588-019-0358-2, Nature Genetics, Nature Genetics, Nature Publishing Group, 2019, 51 (3), pp.414-430. ⟨10.1038/s41588-019-0358-2⟩, Nature genetics 51(3), 414-430 (2019). doi:10.1038/s41588-019-0358-2, Nature genetics
- Publication Year :
- 2019
- Publisher :
- NATURE PUBLISHING GROUP, 2019.
-
Abstract
- Risk for late-onset Alzheimers 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 Alzheimers 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 Alzheimers disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 2009»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.
- Subjects :
- Male
Medizin
Gene Expression
genetics [Alzheimer Disease]
Genome-wide association study
methods [Genome-Wide Association Study]
SEPIA
Genome-wide association studies
genetic meta-analysis
0302 clinical medicine
genetics [Immunity]
genetics [Amyloid beta-Peptides]
genetics
tau
genetics [Genetic Predisposition to Disease]
new risk loci
Aβ
Genetics
Medicine(all)
0303 health sciences
medicine.diagnostic_test
Alzheimer's disease
Lipids
3. Good health
Settore MED/26 - NEUROLOGIA
VINTAGE
Female
Amyloid beta
methods [Genetic Testing]
Tau protein
lipid processing
tau Proteins
genetics [Genetic Loci]
Biology
Article
FR
03 medical and health sciences
Alzheimer Disease
ddc:570
genetics [Haplotypes]
medicine
Genetic predisposition
Humans
Dementia
Genetic Predisposition to Disease
Genetic Testing
LOAD
genetics [Lipids]
Risk factor
immunity
Aged
030304 developmental biology
Genetic testing
Amyloid beta-Peptides
Lipid Metabolism
medicine.disease
Gene expression
genetics [tau Proteins]
Haplotypes
Genetic Loci
Case-Control Studies
genetics [Lipid Metabolism]
genome-wide association studies
biology.protein
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Human medicine
030217 neurology & neurosurgery
Genome-Wide Association Study
dementia
Subjects
Details
- ISSN :
- 10614036 and 15461718
- Database :
- OpenAIRE
- Journal :
- NATURE GENETICS, r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau, instname, Nature Genetics, 51(3), 414-+. Nature Publishing Group, 2019, ' Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing ', Nature Genetics, vol. 51, no. 3, pp. 414-430 . https://doi.org/10.1038/s41588-019-0358-2, Nature Genetics, 51(3), 414-430. Nature Publishing Group, 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 G, Harold, D, Fitzpatrick, A L, Valladares, O, Moutet, M L, Gerrish, A, Smith, A V, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Del Zompo, M, Fox, N C, Choi, S H, 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, Gu, W, 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, Li, S, Huebinger, R M, Kilander, L, Moebus, S, Hernández, I, Kamboh, M I, Brundin, R M, 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, Wu, C K, 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, Ma, L, 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 C, 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 W, 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 H, 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 E, 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 G, 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, Yu, C E, Yu, L, 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 F, Corcoran, C, Ikram, M A, Dickson, D W, Nicolas, G, Campion, D, Tschanz, J A, 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 F, Owen, M J, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, B M, Ramirez, A, Wang, L S, Ruiz, A, van Duijn, C M, Holmans, P A, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, G D, Lambert, J C & Pericak-Vance, M A 2019, ' Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing ', Nature Genetics, vol. 51, no. 3, pp. 414-430 . https://doi.org/10.1038/s41588-019-0358-2, Nature Genetics, Nature Genetics, Nature Publishing Group, 2019, 51 (3), pp.414-430. ⟨10.1038/s41588-019-0358-2⟩, Nature genetics 51(3), 414-430 (2019). doi:10.1038/s41588-019-0358-2, Nature genetics
- Accession number :
- edsair.doi.dedup.....add799dc916d15d988736a5377ca2978