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

Bellenguez, Céline, Küçükali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, de Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcón-Martín, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Álvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antúnez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Pastor, Alfonso Arias, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belén, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Céline, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Mercè, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossù, Paola, Bråthen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Brusco, Luis Ignacio, Buiza-Rueda, Dolores, Bûrger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Geneviève, Chung, Jaeyoon, Cuccaro, Michael L., Carracedo, Ángel, Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. 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R., Clark, Christopher, Conti, Elisa, Corma-Gómez, Anaïs, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-François, de Deyn, Peter Paul, de Paiva Lopes, Katia, de Witte, Lot D., Debette, Stéphanie, Deckert, Jürgen, del Ser, Teodoro, Denning, Nicola, DeStefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Mónica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Düzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernández-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fließbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macías, Emlio, Bullido, María J., Frank-García, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, García-Alberca, Jose Maria, García-González, Pablo, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, González-Pérez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grünblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernández, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Vilas, Raquel Huerto, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Ståhlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleó, Alberto, Longstreth, William, Lopez, Oscar, de Munain, Adolfo Lopez, Love, Seth, Löwemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macías, Juan, MacLeod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquié, Marta, Marshall, Rachel, Martin, Eden R., Montes, Angel Martín, Rodríguez, Carmen Martínez, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menéndez-González, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nöthen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Børge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Pérez-Cordón, Alba, Pérez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. 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David, Gurling, Hugh, Todd, Stephen, Mummery, Catherine, Ryan, Nathalie, Lacidogna, Giordano, Adarmes-Gómez, Ad, Mauleón, Ana, Pancho, Ana, Gailhajenet, Anna, Lafuente, Asunción, Macias-García, D., Martín, Elvira, Pelejà, Esther, Carrillo, F., Merlín, Isabel Sastre, Garrote-Espina, L., Vargas, Liliana, Carrion-Claro, M., Marín, M., Labrador, Ma, Buendia, Mar, Alonso, María Dolores, Guitart, Marina, Moreno, Mariona, Ibarria, Marta, Periñán, Mt, Aguilera, Nuria, Gómez-Garre, P., Cañabate, Pilar, Escuela, R., Pineda-Sánchez, R., Vigo-Ortega, R., Jesús, S., Preckler, Silvia, Rodrigo-Herrero, Silvia, Diego, Susana, Vacca, Alessandro, Roveta, Fausto, Salvadori, Nicola, Chipi, Elena, Boecker, Henning, Laske, Christoph, Perneczky, Robert, Anastasiou, Costas, Janowitz, Daniel, Malik, Rainer, Anastasiou, Anna, Parveen, Kayenat, Lage, Carmen, López-García, Sara, Antonell, Anna, Mihova, Kalina Yonkova, Belezhanska, Diyana, Weber, Heike, Kochen, Silvia, Solis, Patricia, Medel, Nancy, Lisso, 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Pilar, Hevilla, Saray, Jesús, Silvia, Espinosa, Miguel Angel Labrador, Legaz, Agustina, López-García, Sara, Macias-García, Daniel, Manzanares, Salvadora, Marín, Marta, Marín-Muñoz, Juan, Marín, Tamara, Martínez, Begoña, Martínez, Victoriana, Martínez-Lage Álvarez, Pablo, Iriarte, Maite Mendioroz, Periñán-Tocino, María Teresa, Pineda-Sánchez, Rocío, Real de Asúa, Diego, Rodrigo, Silvia, Sastre, Isabel, Vicente, Maria Pilar, Vigo-Ortega, Rosario, Vivancos, Liliana, Epelbaum, Jacques, Hannequin, Didier, campion, Dominique, Deramecourt, Vincent, Tzourio, Christophe, Brice, Alexis, Dubois, Bruno, Williams, Amy, Thomas, Charlene, Davies, Chloe, Nash, William, Dowzell, Kimberley, Morales, Atahualpa Castillo, Bernardo-Harrington, Mateus, Turton, James, Lord, Jenny, Brown, Kristelle, Vardy, Emma, Fisher, Elizabeth, Warren, Jason D., Rossor, Martin, Ryan, Natalie S., Guerreiro, Rita, Uphill, James, Bass, Nick, Heun, Reinhard, Kölsch, Heike, Schürmann, Britta, Lacour, André, Herold, Christine, 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Georgantas, Bob, Heap, Graham, Rahimov, Fedik, Usiskin, Keith, Lu, Tim, Oh, Danny, Kalpala, Kirsi, Miller, Melissa, McCarthy, Linda, Eklund, Kari, Palomäki, Antti, Isomäki, Pia, Pirilä, Laura, Kaipiainen-Seppänen, Oili, Huhtakangas, Johanna, Lertratanakul, Apinya, Hochfeld, Marla, Bing, Nan, Gordillo, Jorge Esparza, Mars, Nina, Pelkonen, Margit, Kauppi, Paula, Kankaanranta, Hannu, Harju, Terttu, Close, David, Greenberg, Steven, Chen, Hubert, Betts, Jo, Ghosh, Soumitra, Salomaa, Veikko, Niiranen, Teemu, Juonala, Markus, Metsärinne, Kaj, Kähönen, Mika, Junttila, Juhani, Laakso, Markku, Pihlajamäki, Jussi, Sinisalo, Juha, Taskinen, Marja-Riitta, Tuomi, Tiinamaija, Challis, Ben, Peterson, Andrew, Chu, Audrey, Parkkinen, Jaakko, Muslin, Anthony, Joensuu, Heikki, Meretoja, Tuomo, Aaltonen, Lauri, Mattson, Johanna, Auranen, Annika, Karihtala, Peeter, Kauppila, Saila, Auvinen, Päivi, Elenius, Klaus, Popovic, Relja, Schutzman, Jennifer, Loboda, Andrey, Chhibber, Aparna, Lehtonen, Heli, 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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Healthcare Sciences Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	11 May 2022
Date of Acceptance:	27 January 2022
Last Modified:	31 Aug 2022 07:37
URI:	https://orca.cardiff.ac.uk/id/eprint/149676

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