New insights into the genetic etiology of Alzheimer's disease and related dementias.
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Authors
Jansen, Iris E
Kleineidam, Luca
Moreno-Grau, Sonia
Naj, Adam C
Campos-Martin, Rafael
Grenier-Boley, Benjamin
Andrade, Victor
Boland, Anne
Damotte, Vincent
Aarsland, Dag
Abdelnour, Carla
Alarcón-Martín, Emilio
Alegret, Montserrat
Álvarez, Victoria
Armstrong, Nicola J
Antúnez, Carmen
Appollonio, Ildebrando
Arcaro, Marina
Archetti, Silvana
Pastor, Alfonso Arias
Arosio, Beatrice
Athanasiu, Lavinia
Bailly, Henri
Banaj, Nerisa
Barral, Sandra
Beiser, Alexa
Below, Jennifer E
Benchek, Penelope
Benussi, Luisa
Besse, Céline
Binetti, Giuliano
Bizarro, Alessandra
Blesa, Rafael
Boerwinkle, Eric
Borroni, Barbara
Boschi, Silvia
Brusco, Luis Ignacio
Buiza-Rueda, Dolores
Bûrger, Katharina
Cantwell, Laura B
Chene, Geneviève
Cuccaro, Michael L
Carracedo, Ángel
Cecchetti, Roberta
Charbonnier, Camille
Chen, Hung-Hsin
Chillotti, Caterina
Ciccone, Simona
Claassen, Jurgen AHR
Clark, Christopher
Conti, Elisa
Corma-Gómez, Anaïs
Custodero, Carlo
Daian, Delphine
Daniele, Antonio
Dardiotis, Efthimios
Dartigues, Jean-François
de Deyn, Peter Paul
Deckert, Jürgen
Denning, Nicola
DeStefano, Anita
Rossi, Paolo Dionigi
Duron, Emmanuelle
Düzel, Emrah
Eiriksdottir, Gudny
Engelborghs, Sebastiaan
Espinosa, Ana
Faber, Kelley M
Nielsen, Sune Fallgaard
Fardo, David W
Farotti, Lucia
Fenoglio, Chiara
Fernández-Fuertes, Marta
Ferrari, Raffaele
Ferreira, Catarina B
Ferri, Evelyn
Fin, Bertrand
Fischer, Peter
Fließbach, Klaus
Fongang, Bernard
Fortea, Juan
Foroud, Tatiana M
Fostinelli, Silvia
Franco-Macías, Emlio
Frank-García, Ana
Fulton-Howard, Brian
García-González, Pablo
Garcia-Madrona, Sebastian
Garcia-Ribas, Guillermo
Ghidoni, Roberta
Giegling, Ina
Giorgio, Giaccone
Goldhardt, Oliver
Gomez-Fonseca, Duber
Graff, Caroline
Grande, Giulia
Grimmer, Timo
Grunin, Michelle
Guetta-Baranes, Tamar
Hadjigeorgiou, Georgios
Haines, Jonathan L
Hamilton-Nelson, Kara L
Hampel, Harald
Hanon, Olivier
Hardy, John
Hartmann, Annette M
Hausner, Lucrezia
Helisalmi, Seppo
Heneka, Michael T
Hernández, Isabel
Hoffmann, Per
Holmes, Clive
Vilas, Raquel Huerto
Hulsman, Marc
Humphrey, Jack
Kauwe, John
Kilander, Lena
Ståhlbom, Anne Kinhult
Kivipelto, Miia
Koivisto, Anne
Kukull, Walter A
Kuksa, Pavel P
Kunkle, Brian W
Kuzma, Amanda B
Laukka, Erika J
Lauria, Alessandra
Lehtisalo, Jenni
Lerch, Ondrej
Longstreth, William
Love, Seth
Löwemark, Malin
Luckcuck, Lauren
Macías, Juan
Maier, Wolfgang
Mangialasche, Francesca
Spallazzi, Marco
Marshall, Rachel
Martin, Eden R
Rodríguez, Carmen Martínez
Masullo, Carlo
Mayeux, Richard
Mecocci, Patrizia
Meggy, Alun
Mehrabian, Shima
Mendoza, Silvia
Mir, Pablo
Moebus, Susanne
Molina-Porcel, Laura
Montrreal, Laura
Morelli, Laura
Moreno, Fermin
Mosley, Thomas
Mukherjee, Shubhabrata
Ngandu, Tiia
Olaso, Robert
Orellana, Adelina
Orsini, Michela
Ortega, Gemma
Padovani, Alessandro
Paolo, Caffarra
Papenberg, Goran
Parnetti, Lucilla
Peters, Oliver
Pijnenburg, Yolande AL
Piñol-Ripoll, Gerard
Polak, Thomas
Popp, Julius
Priller, Josef
Quintela, Inés
Rábano, Alberto
Rainero, Innocenzo
Rajabli, Farid
Ramakers, Inez
Reyes-Dumeyer, Dolly
Ridge, Perry
Riederer, Peter
Roberto, Natalia
Allende, Irene Rosas
Rosende-Roca, Maitée
Royo, Jose Luis
Rubino, Elisa
Rujescu, Dan
Sakka, Paraskevi
Sanabria, Ángela
Sánchez-Arjona, María Bernal
Sanchez-Garcia, Florentino
Sánchez-Valle, Raquel
Sando, Sigrid B
Scamosci, Michela
Scarmeas, Nikolaos
Scarpini, Elio
Scheltens, Philip
Scherbaum, Norbert
Scherer, Martin
Schmid, Matthias
Schneider, Anja
Seripa, Davide
Serrano, Manuel
Sha, Jin
Skrobot, Olivia
Slifer, Susan
Snijders, Gijsje JL
Solomon, Alina
Sorbi, Sandro
Spottke, Annika
Tartan, Juan Pablo
Tárraga, Lluís
Tesí, Niccolo
Thalamuthu, Anbupalam
Thomas, Tegos
Traykov, Latchezar
Tremolizzo, Lucio
Tybjærg-Hansen, Anne
Ullgren, Abbe
Ulstein, Ingun
Valero, Sergi
Vance, Jeffery
Vardarajan, Badri N
van der Lugt, Aad
Dongen, Jasper Van
van Rooij, Jeroen
van Swieten, John
Vandenberghe, Rik
Verhey, Frans
Vyhnalek, Martin
Wang, Li-San
Wang, Ruiqi
Weinhold, Leonie
Windle, Gill
Zhao, Yi
Zhu, Congcong
Zulaica, Miren
EADB
GR@ACE
DEGESCO
EADI
GERAD
Demgene
FinnGen
ADGC
CHARGE
Jessen, Frank
de Mendonça, Alexandre
Hort, Jakub
Clarimon, Jordi
Deleuze, Jean-François
Rossi, Giacomina
Ingelsson, Martin
Hiltunen, Mikko
Schellenberg, Gerard D
Ruiz, Agustín
Publication Date
2022-04Journal Title
Nat Genet
ISSN
1061-4036
Publisher
Springer Science and Business Media LLC
Volume
54
Issue
4
Pages
412-436
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., et al. (2022). New insights into the genetic etiology of Alzheimer's disease and related dementias.. Nat Genet, 54 (4), 412-436. https://doi.org/10.1038/s41588-022-01024-z
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.
Keywords
Humans, Alzheimer Disease, tau Proteins, Genome-Wide Association Study, Cognitive Dysfunction
Sponsorship
Medical Research Council (MR/L023784/1)
Identifiers
35379992, PMC9005347
External DOI: https://doi.org/10.1038/s41588-022-01024-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336901
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