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

Céline Bellenguez Orcid Logo, Fahri Küçükali Orcid Logo, Iris E. Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin Orcid Logo, Adam C. Naj, Rafael Campos-Martin, Benjamin Grenier-Boley, Victor Andrade, Peter A. Holmans Orcid Logo, Anne Boland, Vincent Damotte, Sven J. van der Lee Orcid Logo, Marcos R. Costa Orcid Logo, Teemu Kuulasmaa Orcid Logo, Qiong Yang Orcid Logo, Itziar de Rojas Orcid Logo, Joshua C. Bis Orcid Logo, Amber Yaqub Orcid Logo, Ivana Prokic Orcid Logo, Julien Chapuis Orcid Logo, Shahzad Ahmad Orcid Logo, Vilmantas Giedraitis Orcid Logo, Dag Aarsland, Pablo Garcia-Gonzalez Orcid Logo, Carla Abdelnour, Emilio Alarcón-Martín, Daniel Alcolea Orcid Logo, Montserrat Alegret, Ignacio Alvarez Orcid Logo, Victoria Álvarez, Nicola J. Armstrong, Anthoula Tsolaki Orcid Logo, Carmen Antúnez, Ildebrando Appollonio, Marina Arcaro, Silvana Archetti, Alfonso Arias Pastor, Beatrice Arosio, Lavinia Athanasiu, Henri Bailly, Nerisa Banaj, Miquel Baquero Orcid Logo, Sandra Barral, Alexa Beiser, Ana Belén Pastor Orcid Logo, Jennifer E. Below, Penelope Benchek, Luisa Benussi, Claudine Berr Orcid Logo, Céline Besse, Valentina Bessi Orcid Logo, Giuliano Binetti, Alessandra Bizarro, Rafael Blesa, Mercè Boada Orcid Logo, Eric Boerwinkle, Barbara Borroni, Silvia Boschi, Paola Bossù Orcid Logo, Geir Bråthen Orcid Logo, Jan Bressler Orcid Logo, Catherine Bresner Orcid Logo, Henry Brodaty Orcid Logo, Keeley J. Brookes Orcid Logo, Luis Ignacio Brusco, Dolores Buiza-Rueda, Katharina Bûrger, Vanessa Burholt Orcid Logo, William S. Bush Orcid Logo, Miguel Calero Orcid Logo, Laura B. Cantwell, Geneviève Chene, Jaeyoon Chung Orcid Logo, Michael L. Cuccaro, Ángel Carracedo, Roberta Cecchetti, Laura Cervera-Carles Orcid Logo, Camille Charbonnier, Hung-Hsin Chen, Caterina Chillotti, Simona Ciccone, Jurgen A. H. R. Claassen, Christopher Clark, Elisa Conti, Anaïs Corma-Gómez, Emanuele Costantini Orcid Logo, Carlo Custodero, Delphine Daian, Maria Carolina Dalmasso Orcid Logo, Antonio Daniele, Efthimios Dardiotis, Jean-François Dartigues, Peter Paul de Deyn, Katia de Paiva Lopes Orcid Logo, Lot D. de Witte Orcid Logo, Stéphanie Debette Orcid Logo, Jürgen Deckert, Teodoro del Ser Orcid Logo, Nicola Denning, Anita DeStefano, Martin Dichgans Orcid Logo, Janine Diehl-Schmid Orcid Logo, Mónica Diez-Fairen Orcid Logo, Paolo Dionigi Rossi, Srdjan Djurovic Orcid Logo, Emmanuelle Duron, Emrah Düzel, Carole Dufouil Orcid Logo, Gudny Eiriksdottir, Sebastiaan Engelborghs, Valentina Escott-Price Orcid Logo, Ana Espinosa, Michael Ewers Orcid Logo, Kelley M. Faber, Tagliavini Fabrizio Orcid Logo, Sune Fallgaard Nielsen, David W. Fardo, Lucia Farotti, Chiara Fenoglio, Marta Fernández-Fuertes, Raffaele Ferrari, Catarina B. Ferreira, Evelyn Ferri, Bertrand Fin, Peter Fischer, Tormod Fladby Orcid Logo, Klaus Fließbach, Bernard Fongang, Myriam Fornage Orcid Logo, Juan Fortea, Tatiana M. Foroud, Silvia Fostinelli, Nick C. Fox Orcid Logo, Emlio Franco-Macías, María J. Bullido Orcid Logo, Ana Frank-García, Lutz Froelich Orcid Logo, Brian Fulton-Howard, Daniela Galimberti Orcid Logo, Jose Maria García-Alberca Orcid Logo, Pablo García-González, Sebastian Garcia-Madrona, Guillermo Garcia-Ribas, Roberta Ghidoni, Ina Giegling, Giaccone Giorgio, Alison M. Goate Orcid Logo, Oliver Goldhardt, Duber Gomez-Fonseca, Antonio González-Pérez Orcid Logo, Caroline Graff, Giulia Grande, Emma Green Orcid Logo, Timo Grimmer, Edna Grünblatt Orcid Logo, Michelle Grunin, Vilmundur Gudnason Orcid Logo, Tamar Guetta-Baranes, Annakaisa Haapasalo Orcid Logo, Georgios Hadjigeorgiou, Jonathan L. Haines, Kara L. Hamilton-Nelson, Harald Hampel, Olivier Hanon, John Hardy, Annette M. Hartmann, Lucrezia Hausner, Janet Harwood Orcid Logo, Stefanie Heilmann-Heimbach Orcid Logo, Seppo Helisalmi, Michael T. Heneka, Isabel Hernández, Martin J. Herrmann Orcid Logo, Per Hoffmann, Clive Holmes, Henne Holstege Orcid Logo, Raquel Huerto Vilas, Marc Hulsman, Jack Humphrey, Geert Jan Biessels Orcid Logo, Xueqiu Jian Orcid Logo, Charlotte Johansson Orcid Logo, Gyungah R. Jun Orcid Logo, Yuriko Kastumata Orcid Logo, John Kauwe, Patrick G. Kehoe Orcid Logo, Lena Kilander, Anne Kinhult Ståhlbom, Miia Kivipelto, Anne Koivisto, Johannes Kornhuber Orcid Logo, Mary H. Kosmidis Orcid Logo, Walter A. Kukull, Pavel P. Kuksa, Brian W. Kunkle, Amanda B. Kuzma, Carmen Lage Orcid Logo, Erika J. Laukka, Lenore Launer Orcid Logo, Alessandra Lauria, Chien-Yueh Lee Orcid Logo, Jenni Lehtisalo, Ondrej Lerch, Alberto Lleó Orcid Logo, William Longstreth, Oscar Lopez Orcid Logo, Adolfo Lopez de Munain Orcid Logo, Seth Love, Malin Löwemark, Lauren Luckcuck, Kathryn L. Lunetta Orcid Logo, Yiyi Ma Orcid Logo, Juan Macías, Catherine A. MacLeod Orcid Logo, Wolfgang Maier, Francesca Mangialasche, Marco Spallazzi, Marta Marquié Orcid Logo, Rachel Marshall, Eden R. Martin, Angel Martín Montes Orcid Logo, Carmen Martínez Rodríguez, Carlo Masullo, Richard Mayeux, Simon Mead Orcid Logo, Patrizia Mecocci, Miguel Medina Orcid Logo, Alun Meggy, Shima Mehrabian, Silvia Mendoza, Manuel Menéndez-González Orcid Logo, Pablo Mir, Susanne Moebus, Merel Mol Orcid Logo, Laura Molina-Porcel, Laura Montrreal, Laura Morelli, Fermin Moreno, Kevin Morgan Orcid Logo, Thomas Mosley, Markus M. Nöthen Orcid Logo, Carolina Muchnik Orcid Logo, Shubhabrata Mukherjee, Benedetta Nacmias Orcid Logo, Tiia Ngandu, Gael Nicolas Orcid Logo, Børge G. Nordestgaard Orcid Logo, Robert Olaso, Adelina Orellana, Michela Orsini, Gemma Ortega, Alessandro Padovani, Caffarra Paolo, Goran Papenberg, Lucilla Parnetti, Florence Pasquier Orcid Logo, Pau Pastor Orcid Logo, Gina Peloso Orcid Logo, Alba Pérez-Cordón Orcid Logo, Jordi Pérez-Tur Orcid Logo, Pierre Pericard Orcid Logo, Oliver Peters, Yolande A. L. Pijnenburg, Juan A. Pineda Orcid Logo, Gerard Piñol-Ripoll, Claudia Pisanu Orcid Logo, Thomas Polak, Julius Popp, Danielle Posthuma Orcid Logo, Josef Priller, Raquel Puerta Orcid Logo, Olivier Quenez Orcid Logo, Inés Quintela, Jesper Qvist Thomassen Orcid Logo, Alberto Rábano, Innocenzo Rainero, Farid Rajabli, Inez Ramakers, Luis M. Real Orcid Logo, Marcel J. T. Reinders Orcid Logo, Christiane Reitz Orcid Logo, Dolly Reyes-Dumeyer, Perry Ridge, Steffi Riedel-Heller Orcid Logo, Peter Riederer, Natalia Roberto, Eloy Rodriguez-Rodriguez Orcid Logo, Arvid Rongve Orcid Logo, Irene Rosas Allende, Maitée Rosende-Roca, Jose Luis Royo, Elisa Rubino, Dan Rujescu, María Eugenia Sáez Orcid Logo, Paraskevi Sakka, Ingvild Saltvedt Orcid Logo, Ángela Sanabria, María Bernal Sánchez-Arjona, Florentino Sanchez-Garcia, Pascual Sánchez Juan Orcid Logo, Raquel Sánchez-Valle, Sigrid B. Sando, Chloé Sarnowski Orcid Logo, Claudia L. Satizabal Orcid Logo, Michela Scamosci, Nikolaos Scarmeas, Elio Scarpini, Philip Scheltens, Norbert Scherbaum, Martin Scherer, Matthias Schmid, Anja Schneider, Jonathan M. Schott Orcid Logo, Geir Selbæk Orcid Logo, Davide Seripa, Manuel Serrano, Jin Sha, Alexey A. Shadrin Orcid Logo, Olivia Skrobot, Susan Slifer, Gijsje J. L. Snijders, Hilkka Soininen Orcid Logo, Vincenzo Solfrizzi Orcid Logo, Alina Solomon, Yeunjoo Song Orcid Logo, Sandro Sorbi, Oscar Sotolongo-Grau Orcid Logo, Gianfranco Spalletta Orcid Logo, Annika Spottke, Alessio Squassina Orcid Logo, Eystein Stordal Orcid Logo, Juan Pablo Tartan, Lluís Tárraga, Niccolo Tesí, Anbupalam Thalamuthu, Tegos Thomas, Giuseppe Tosto Orcid Logo, Latchezar Traykov, Lucio Tremolizzo, Anne Tybjærg-Hansen, Andre Uitterlinden Orcid Logo, Abbe Ullgren, Ingun Ulstein, Sergi Valero, Otto Valladares Orcid Logo, Christine Van Broeckhoven Orcid Logo, Jeffery Vance, Badri N. Vardarajan, Aad van der Lugt, Jasper Van Dongen, Jeroen van Rooij, John van Swieten, Rik Vandenberghe, Frans Verhey, Jean-Sébastien Vidal Orcid Logo, Jonathan Vogelgsang Orcid Logo, Martin Vyhnalek, Michael Wagner Orcid Logo, David Wallon Orcid Logo, Li-San Wang, Ruiqi Wang, Leonie Weinhold, Jens Wiltfang Orcid Logo, Gill Windle, Bob Woods Orcid Logo, Mary Yannakoulia Orcid Logo, Habil Zare Orcid Logo, Yi Zhao, Xiaoling Zhang Orcid Logo, Congcong Zhu, Miren Zulaica, Jan Laczo, Vaclav Matoska, Maria Serpente, Francesca Assogna, Fabrizio Piras, Federica Piras, Valentina Ciullo, Jacob Shofany, Carlo Ferrarese, Simona Andreoni, Gessica Sala, Chiara Paola Zoia, Maria Del Zompo, Alberto Benussi, Patrizia Bastiani, Mari Takalo, Teemu Natunen, Tiina Laatikainen, Jaakko Tuomilehto, Riitta Antikainen, Timo Strandberg, Jaana Lindström, Markku Peltonen, Richard Abraham, Ammar Al-Chalabi, Nicholas J. Bass, Carol Brayne, Kristelle S. Brown, John Collinge, David Craig, Pangiotis Deloukas, Nick Fox, Amy Gerrish, Michael Gill, Rhian Gwilliam, Denise Harold, Paul Hollingworth, Jarret A. Johnston, Lesley Jones, Brian Lawlor, Gill Livingston, Simon Lovestone, Michelle Lupton, Aoibhinn Lynch, David Mann, Bernadette McGuinness, Andrew McQuillin, Michael C. O’Donovan, Michael J. Owen, Peter Passmore, John F. Powell, Petra Proitsi, Martin Rossor, Christopher E. Shaw, A. David Smith, Hugh Gurling, Stephen Todd, Catherine Mummery, Nathalie Ryan, Giordano Lacidogna, Ad Adarmes-Gómez, Ana Mauleón, Ana Pancho, Anna Gailhajenet, Asunción Lafuente, D. Macias-García, Elvira Martín, Esther Pelejà, F. Carrillo, Isabel Sastre Merlín, L. Garrote-Espina, Liliana Vargas, M. Carrion-Claro, M. Marín, Ma Labrador, Mar Buendia, María Dolores Alonso, Marina Guitart, Mariona Moreno, Marta Ibarria, Mt Periñán, Nuria Aguilera, P. Gómez-Garre, Pilar Cañabate, R. Escuela, R. Pineda-Sánchez, R. Vigo-Ortega, S. 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Nature Genetics, Volume: 54, Issue: 4, Pages: 412 - 436

Swansea University Author: Vanessa Burholt Orcid Logo

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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/‘pro...

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Published in: Nature Genetics
ISSN: 1061-4036 1546-1718
Published: Springer Science and Business Media LLC 2022
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa60592
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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.
College: College of Human and Health Sciences
Funders: This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD).
Issue: 4
Start Page: 412
End Page: 436