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New insights on the genetic etiology of Alzheimer and related dementia

By Celine Bellenguez, Fahri Kucukali, Iris Jansen, Victor Andrade, Sonia Morenau-Grau, Najaf Amin, Adam Naj, Benjamin Grenier-Boley, Rafael Campos Martin, Peter Holsman, Anne Boland, Luca Kleideman, Vincent Damotte, Sven Vander Lee, Pablo Garcia, Yang Qiong, Joshua C. Bis, Marcos Costa, Julien Chapuis, Vilmentas Giedraitis, Maria J Bullido, Adolfo Lopez de Munain, Jordi Perez-Tur, Pascual Sanchez-Juan, Raquel Sanchez-Valle, Victoria Alvarez, Pau Pastor, Miguel Medina, Jasper Van Dongen, Christine Van Broeckhoven, Rik Vandenberghe, Sebastiaan Engelborghs, Gael Nicolas, Florence Pasquier, Olivier Hanon, Carole Dufouil, Claudine Berr, Stephanie Debette, Jean-Francois Dartigues, Gianfranco Spalletta, Benedetta Nacmias, Vincenzo Solfrezzi, Barbara Berroni, Lucio Tremolizzo, Davide Seripa, Paolo Caffara, Antonio Daniele, Daniela Galimberti, Innocenzo Rainero, Luisa Benussi, Alesio Squassina, Patricia Mecoci, Lucilla Parnetti, Carlo Masullo, Beatrice Arosio, John Hardy, Simon Mead, Kevin Morgan, Clive Holmes, Patrick Kehoe, Bob Woods, EADB consortium, Charge Consortium, ADGC Consortium, Jin Sha, Yi Zhao, Chien-Yueh Lee, Pavel p Kuksa, Kara L Hamilton-Nelson, Brian Kunkle, William S Bush, Eden R. Martin, Li-San Wang, Richard Mayeux, Lindsay A. Farrer, Jonathan L. Haines, Ruiqi Wang, Claudia Satizabal, Bruce Psaty, Oscar Lopez, Florentino Sanchez-Garcia, Borge G Nordestgaard, Anne Tybjaeg-hansen, Jesper Qvist Thomassen, Caroline Graff, Goran Papenberg, Hilkka Soininen, Miia Kivipelto, Annakaisa Haapasalo, Tiia Ngandu, Anne Koivisto, Teemu Kuulasmaa, Laura Molina Porcel, Johannes Kornhuber, Oliver Peters, Anja Schneider, Nikolaos Scarmeas, Martin Dichgans, Lutz Froelich, Dan Rujescu, Janine Diehl-Schmid, Timo Grimmer, Matthias Schmid, Markus M Mothen, Edna Grunblatt, Julius Popp, Norbert Scherbaum, Shima Mehrabian, Deckert Jurgen, dag Aareland, Geir Selbaeck, Ingvild Saltvedt, Srdjan Djurovic, Henne Holstege, Yolande A.L. Pijnenburg, John Van Swieten, Inez Ramakers, Aad Van der Lugt, Jurgen A.H.R. Claassen, Geert Jan Biessels, Philip Scheltens, Carmen Antunez, Pablo Mir, Luis Miguel Real, Jose Maria Garcia-Alberca, Gerard Pinol-Ripoll, Guillermo Garcia-Ribas, Manuel Serrano-Rios, Franck Jessen, Alexandre de Mendoca, Jakub Hort, Margaret A. Pericak-Vance, Magda Tsolaki, Philippe Amouyel, Julie Williams, Ruth Frikke-Schmidt, Jordi Clarimon, Jean-Francois Deleuze, Giacomina Rossi, Sudha Seshadri, Ole Andreassen, Martin Ingelsson, Mikko Hiltunen, Kristel Sleegers, Gerald SChellenberg, Cornelia Van Duijn, Rebecca Sims, Wiesje Van der Flier, Agustin Ruiz, Alfredo Ramirez, Jean-Charles Lambert

Posted 04 Oct 2020
medRxiv DOI: 10.1101/2020.10.01.20200659

Alzheimer disease (AD) is a severe and incurable neurodegenerative disease, and the failure to find effective treatments suggests that the underlying pathology remains poorly understood. Due to its strong heritability, deciphering the genetic landscape of AD and related dementia (ADD) is a unique opportunity to advance our knowledge. We completed a meta-analysis of genome-wide association studies (39,106 clinically AD-diagnosed cases, 46,828 proxy-ADD cases and 401,577 controls) with the most promising signals followed-up in 25,392 independent AD cases and 276,086 controls. We report 75 risk loci for ADD, including 42 novel ones. Pathway-enrichment analyses confirm the involvement of amyloid/Tau pathways, highlight the role of microglia and its potential interaction with APP metabolism. Numerous genes exhibited differential expression or splicing in AD-related conditions and gene prioritization implies EGFR signaling and TNFapha pathway through LUBAC complex. We also generated a novel polygenic risk score strongly associated with the risk of future dementia or progression from mild cognitive impairment to dementia. In conclusion, by more than doubling the number of loci associated with ADD risk, our study offers new insights into the pathophysiological processes underlying AD and offers additional therapeutic entry-points and tools for translational genomics

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