New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'pro...

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Autores: Bellenguez, Céline|||0000-0002-1240-7874; Küçükali, Fahri; Jansen, Iris E.|||0000-0003-1901-8131; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf|||0000-0002-8944-1771; Naj, Adam C.|||0000-0002-9621-2942; Campos-Martin, Rafael|||0000-0002-1395-8571; Grenier-Boley, Benjamin; Andrade, Victor|||0000-0003-0682-269X; Holmans, Peter|||0000-0003-0870-9412; Boland, Anne|||0000-0001-8789-5676; Damotte, Vincent|||0000-0002-7321-8575; van der Lee, Sven J.|||0000-0003-1606-8643; Costa, Marcos R.|||0000-0002-4928-2163; Kuulasmaa, Teemu|||0000-0002-1795-7314; Yang, Qiong|||0000-0002-3658-1375; De Rojas, Itziar|||0000-0002-2148-381X; Bis, Joshua C.|||0000-0002-3409-1110; Yaqub, Amber|||0000-0002-3579-8054; Prokic, Ivana|||0000-0002-0370-1473; Chapuis, Julien|||0000-0002-5802-2857; Ahmad, Shahzad|||0000-0002-8658-3790; Giedraitis, Vilmantas|||0000-0003-3423-2021; Aarsland, Dag|||0000-0001-6314-216X; García-González, Pablo|||0000-0003-0125-5403; Abdelnour, Carla|||0000-0002-7636-9758; Alarcón-Martín, Emilio|||0000-0002-0985-872X; Alcolea, Daniel|||0000-0002-3819-3245; Alegret, Montserrat|||0000-0002-8164-9500; Alvarez, Ignacio|||0000-0002-8537-3935; Alvarez, Victoria|||0000-0002-1916-2523; Armstrong, Nicola|||0000-0002-4477-293X; Tsolaki, Anthoula|||0000-0002-5563-7776; Antúnez, Carmen; Appollonio, Ildebrando; Arcaro, Marina|||0000-0002-3821-0682; Archetti, Silvana; Pastor, Alfonso A.; Arosio, Beatrice|||0000-0002-0615-3580; Athanasiu, Lavinia; Bailly, Henri; Banaj, Nerisa|||0000-0002-6317-8549; Baquero, Miquel|||0000-0002-6861-1831; Barral, Sandra; Beiser, Alexa; Pastor, Ana Belén|||0000-0001-9637-4688; Below, Jennifer E.; Benchek, Penelope; Benussi, Luisa|||0000-0003-2836-8141; Berr, Claudine|||0000-0001-5254-7655; Besse, Céline; Bessi, Valentina|||0000-0002-6176-3584; Binetti, Giuliano|||0000-0003-2759-5844; Bizarro, Alessandra; Blesa, Rafael|||0000-0003-4026-2884; Boada, Mercè|||0000-0003-2617-3009; Boerwinkle, Eric|||0000-0001-8813-0544; Borroni, Barbara|||0000-0001-9340-9814; Boschi, Silvia|||0000-0003-1610-1917; Bossù, Paola|||0000-0002-1432-0078; Bråthen, Geir|||0000-0003-3224-7983; Bressler, Jan|||0000-0001-6578-4772; Bresner, Catherine|||0000-0003-2673-9762; Brodaty, Henry|||0000-0001-9487-6617; Brookes, Keeley J.|||0000-0003-2427-2513; Brusco, Luis Ignacio; Buiza-Rueda, Dolores|||0000-0002-3504-9299; Bûrger, Katharina; Burholt, Vanessa|||0000-0002-6789-127X; Bush, William|||0000-0002-9729-6519; Calero, Miguel|||0000-0001-5366-3324; Cantwell, Laura B.; Chene, Geneviève|||0000-0002-8368-6460; Chung, Jaeyoon|||0000-0002-6431-9454; Frosch, M.P.; Fulton-Howard, B.; Galasko, D.R.; Gamboa, A.; Gearing, M.; Geschwind, D.H.; Ghetti, Bernardino|||0000-0002-1842-8019; Cuccaro, MichaelL.; Gilbert, J.R.; Grabowski, T.J.; Graff-Radford, N.R.; Grant, S.F.A.; Green, R.C.; Growdon, J.H.; Haines, J.L.; Hakonarson, Hakon|||0000-0003-2814-7461; Hall, J.; Hamilton, R.L.; Carracedo, Ángel|||0000-0003-1085-8986; Harari, O.; Harrell, L.E.; Haut, J.; Head, Elizabeth|||0000-0003-1115-6396; Henderson, V.W.; Hernandez, M.; Hohman, T.; Honig, L.S.; Huebinger, R.M.; Huentelman, M.J.; Cecchetti, Roberta; Hulette, C.M.; Hyman, B.T.; Hynan, L.S.; Ibanez, L.; Jarvik, G.P.; Jayadev, S.; Jin, L.W.; Johnson, K.; Johnson, Leigh A.; Kamboh, M.I.; Cervera Carles, Laura|||0000-0003-2286-200X; Karydas, A.M.; Katz, M.J.; Kaye, J.A.; Keene, C.D.; Khaleeq, A.; Kim, R.; Knebl, J.; Kowall, N.W.; Kramer, J.H.; Kuksa, P.P.; Charbonnier, Camille|||0000-0003-1172-0196; LaFerla, Frank M.|||0000-0003-2324-6911; Lah, J.J.; Larson, E.B.; Lee, C.Y.|||0000-0002-4304-974X; Lee, E.B.; Lerner, A.; Leung, Y.Y.; Leverenz, J.B.; Levey, A.I.; Li, Mengyao|||0000-0002-9082-7938; Chen, Hung-Hsin; Lieberman, A.P.; Lipton, R.B.; Logue, M.; Lyketsos, C.G.; Malamon, J.; Mains, D.; Marson, D.C.; Martiniuk, F.; Mash, D.C.; Masliah, E.; Chillotti, Caterina; Massman, P.; Masurkar, A.; McCormick, W.C.; McCurry, S.M.; McDavid, A.N.; McDonough, S.; McKee, A.C.; Mesulam, M.; Mez, J.; Miller, B.L.; Ciccone, Simona; Miller, C.A.; Miller, J.W.; Montine, T.J.; Monuki, E.S.; Morris, J.C.; Myers, A.J.; Nguyen, Thanh N.|||0000-0002-2810-1685; O'Bryant, S.; Olichney, J.M.; Ory, M.; Claassen, Jurgen A. H. R.; Palmer, R.; Parisi, J.E.; Paulson, H.L.; Pavlik, V.; Paydarfar, D.; Pérez Solà, Víctor|||0000-0002-5825-2337; Peskind, E.; Phillips-Cremins, J.E.; Pierce, A.; Polk, M.; Clark, Christopher|||0000-0001-7210-7702; Poon, W.W.; Potter, H.; Qu, L.; Quiceno, M.; Quinn, J.F.; Raj, A.; Raskind, M.; Reiman, E.M.; Reisberg, B.; Reisch, J.S.; Conti, Elisa; Ringman, J.M.; Roberson, E.D.; Rodriguear, M.; Rogaeva, Ekaterina; Rosen, H.J.; Rosenberg, R.N.; Royall, D.R.; Sager, M.A.; Sano, M.; Saykin, A.J.; Corma Gómez, Anaïs|||0000-0002-1078-0237; Schneider, J.A.; Schneider, L.S.; Seeley, W.W.; Slifer, S.H.; Small, S.; Smith, A.G.; Smith, J.P.; Song, Y.E.; Sonnen, J.A.; Spina, S.; Costantini, Emanuele|||0000-0002-1096-8221; St George Hyslop, Peter|||0000-0003-0796-7209; Stern, R.A.; Stevens, A.B.; Strittmatter, S.M.; Sultzer, D.; Swerdlow, R.H.; Tanzi, Rudolph E.|||0000-0002-7032-1454; Tilson, J.L.; Trojanowski, John Q.|||0000-0002-9239-8794; Troncoso, J.C.; Custodero, Carlo|||0000-0003-1549-6451; Tsuang, D.W.; Valladares, Otto|||0000-0001-8055-2187; Van Deerlin, V.M.; van Eldik, L.J.; Vassar, R.; Vinters, H.V.; Vonsattel, J.P.; Weintraub, S.; Welsh-Bohmer, K.A.; Whitehead, P.L.; Daian, Delphine; Wijsman, E.M.; Wilhelmsen, K.C.; Williams, B.; Williamson, J.; Wilms, H.; Wingo, T.S.; Wisniewski, Thomas M.; Woltjer, Randy L.; Woon, M.; Wright, C.B.; Dalmasso, Maria Carolina|||0000-0002-4901-9955; Wu, C.K.; Younkin, Steven G.; Yu, C.E.; Yu, L.; Zhang, Yu|||0000-0002-0332-0013; Zhao, Y.; Zhu, X.|||0000-0003-0037-411X; Adams, Hieab H. H.|||0000-0003-3687-2508; Akinyemi, Rufus; Ali, M.; Daniele, Antonio|||0000-0003-1641-5852; Aparicio, H.J.; Bahadori, M.; Becker, James T.|||0000-0003-4425-4726; Breteler, M.; Chasman, D.; Chauhan, G.; Comic, H.; Cox, S.; Cupples, A.L.; Davies, Gail; Dardiotis, Efthimios|||0000-0003-2957-641X; DeCarli, C.S.; Duperron, M.G.; Dupuis, J.; Evans, T.; Fan, F.; Fitzpatrick, A.; Fohner, A.E.; Ganguli, M.; Geerlings, M.; Glatt, Stephen J.|||0000-0002-0360-7567; Dartigues, Jean-François; Gonzalez, H.M.; Goss, M.; Grabe, H.; Habes, M.; Heckbert, S.R.; Hofer, E.; Hong, E.; Hughes, T.; Kautz, T.F.; Knol, M.; De Deyn, Peter Paul|||0000-0002-2228-2964; Kremen, W.; Lacaze, Paul|||0000-0002-0902-6798; Lahti, J.; Grand, Q.L.; Litkowski, E.; Li, S.; Liu, Daijun|||0000-0002-0993-0832; Liu, X.; Loitfelder, M.; Manning, A.; de Paiva Lopes, Katia|||0000-0002-0240-0126; Maillard, P.; Marioni, R.; Mazoyer, B.; van Lent, D.M.; Mei, H.; Mishra, Aniket|||0000-0002-8141-1543; Nyquist, P.; O'Connell, J.; Patel, Y.; Paus, T.; de Witte, Lot D.|||0000-0002-7235-9958; Pausova, Z.; Raikkonen-Talvitie, K.; Riaz, M.; Rich, S.; Romero, J.; Roshchupkin, G.; Saba, Y.; Sargurupremraj, M.; Schmidt, H.; Schmidt, Reinhold; Debette, Stéphanie|||0000-0001-8675-7968; Shulman, J.M.; Smith, J.; Sekhar, H.; Rajula, R.; Shin, J.; Simino, J.; Sliz, E.; Teumer, A.; Thomas, A.; Tin, A.; Deckert, Jürgen|||0000-0003-1008-4650; Tucker-Drob, E.; Vojinovic, Dina; Wang, Yanbing; Weinstein, Galit; Williams, Dylan; Wittfeld, Katharina|||0000-0003-4383-5043; Yanek, Lisa R.|||0000-0001-7117-1075; Yang, Yunju; Farrer, L.A.; Psaty, B.M.; del Ser, Teodoro|||0000-0001-9806-7083; Ghanbari, M.|||0000-0002-9476-7143; Raj, T.; Sachdev, Perminder S.|||0000-0002-9595-3220; Mather, Karen A.|||0000-0003-4143-8941; Jessen, Frank; Ikram, M. Arfan|||0000-0003-0372-8585; de Mendonça, Alexandre|||0000-0002-0488-1453; Hort, J.; Tsolaki, Magda|||0000-0002-2072-8010; Pericak-Vance, Margaret A.|||0000-0001-7283-8804; Denning, Nicola|||0000-0001-8467-7382; Amouyel, Philippe|||0000-0001-9088-234X; Williams, J.; Frikke-Schmidt, Ruth|||0000-0003-4084-5027; Clarimón, Jordi|||0000-0002-6824-6942; Deleuze, J.F.|||0000-0002-5358-4463; Rossi, Giacomina|||0000-0001-6680-2725; Seshadri, S.; Andreassen, Ole A.|||0000-0002-4461-3568; Ingelsson, Martin|||0000-0001-5466-8370; Hiltunen, M.; DeStefano, Anita L.|||0000-0002-9335-2819; Sleegers, Kristel|||0000-0002-0283-2332; Schellenberg, G.D.; van Duijn, C.M.; Sims, Rebecca|||0000-0002-3885-1199; van der Flier, Wiesje M.|||0000-0001-8766-6224; Ruiz Laza, Agustín|||0000-0003-2633-2495; Ramirez, Alfredo|||0000-0003-4991-763X; Lambert, Jean-Charles|||0000-0003-0829-7817; Dichgans, Martin|||0000-0002-0654-387X
Tipo de documento: Artigo
Data de publicação:2022
País:España
Recursos:Universitat Autònoma de Barcelona
Repositório:Dipòsit Digital de Documents de la UAB
Idioma:Inglês
OAI Identifier:oai:ddd.uab.cat:275184
Acesso em linha:https://ddd.uab.cat/record/275184
https://dx.doi.org/urn:doi:10.1038/s41588-022-01024-z
Nível de acesso:Acesso aberto
Palavra-chave:Alzheimer Disease
Cognitive Dysfunction
Genome-Wide Association Study
Humans
Tau Proteins
Descrição
Resumo:Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.