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.
Original language | English |
---|---|
Pages (from-to) | 412-436 |
Number of pages | 25 |
Journal | Nature Genetics |
Volume | 54 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2022 |
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In: Nature Genetics, Vol. 54, No. 4, 01.04.2022, p. 412-436.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - New insights into the genetic etiology of Alzheimer’s disease and related dementias
AU - EADB
AU - GR@ACE
AU - DEGESCO
AU - EADI
AU - GERAD
AU - Demgene
AU - FinnGen
AU - ADGC
AU - CHARGE
AU - Bellenguez, Céline
AU - Küçükali, Fahri
AU - Jansen, Iris E.
AU - Kleineidam, Luca
AU - Moreno-Grau, Sonia
AU - Amin, Najaf
AU - Naj, Adam C.
AU - Campos-Martin, Rafael
AU - Grenier-Boley, Benjamin
AU - Andrade, Victor
AU - Holmans, Peter A.
AU - Boland, Anne
AU - Damotte, Vincent
AU - van der Lee, Sven J.
AU - Costa, Marcos R.
AU - Kuulasmaa, Teemu
AU - Yang, Qiong
AU - de Rojas, Itziar
AU - Bis, Joshua C.
AU - Yaqub, Amber
AU - Prokic, Ivana
AU - Chapuis, Julien
AU - Ahmad, Shahzad
AU - Giedraitis, Vilmantas
AU - Aarsland, Dag
AU - Garcia-Gonzalez, Pablo
AU - Abdelnour, Carla
AU - Alarcón-Martín, Emilio
AU - Alcolea, Daniel
AU - Alegret, Montserrat
AU - Alvarez, Ignacio
AU - Álvarez, Victoria
AU - Armstrong, Nicola J.
AU - Tsolaki, Anthoula
AU - Antúnez, Carmen
AU - Appollonio, Ildebrando
AU - Arcaro, Marina
AU - Archetti, Silvana
AU - Pastor, Alfonso Arias
AU - Arosio, Beatrice
AU - Athanasiu, Lavinia
AU - Bailly, Henri
AU - Banaj, Nerisa
AU - Baquero, Miquel
AU - Barral, Sandra
AU - Beiser, Alexa
AU - Pastor, Ana Belén
AU - Below, Jennifer E.
AU - Benchek, Penelope
AU - Benussi, Luisa
AU - Berr, Claudine
AU - Besse, Céline
AU - Bessi, Valentina
AU - Binetti, Giuliano
AU - Bizarro, Alessandra
AU - Blesa, Rafael
AU - Boada, Mercè
AU - Boerwinkle, Eric
AU - Borroni, Barbara
AU - Boschi, Silvia
AU - Bossù, Paola
AU - Bråthen, Geir
AU - Bressler, Jan
AU - Bresner, Catherine
AU - Brodaty, Henry
AU - Brookes, Keeley J.
AU - Brusco, Luis Ignacio
AU - Buiza-Rueda, Dolores
AU - Bûrger, Katharina
AU - Burholt, Vanessa
AU - Bush, William S.
AU - Calero, Miguel
AU - Cantwell, Laura B.
AU - Chene, Geneviève
AU - Chung, Jaeyoon
AU - Cuccaro, Michael L.
AU - Carracedo, Ángel
AU - Cecchetti, Roberta
AU - Cervera-Carles, Laura
AU - Charbonnier, Camille
AU - Chen, Hung Hsin
AU - Chillotti, Caterina
AU - Ciccone, Simona
AU - Claassen, Jurgen A.H.R.
AU - Clark, Christopher
AU - Conti, Elisa
AU - Corma-Gómez, Anaïs
AU - Costantini, Emanuele
AU - Custodero, Carlo
AU - Daian, Delphine
AU - Dalmasso, Maria Carolina
AU - Daniele, Antonio
AU - Dardiotis, Efthimios
AU - Dartigues, Jean François
AU - de Deyn, Peter Paul
AU - de Paiva Lopes, Katia
AU - de Witte, Lot D.
AU - Debette, Stéphanie
AU - Deckert, Jürgen
AU - del Ser, Teodoro
AU - Denning, Nicola
AU - DeStefano, Anita
AU - Dichgans, Martin
AU - Diehl-Schmid, Janine
AU - Diez-Fairen, Mónica
AU - Rossi, Paolo Dionigi
AU - Djurovic, Srdjan
AU - Duron, Emmanuelle
AU - Düzel, Emrah
AU - Dufouil, Carole
AU - Eiriksdottir, Gudny
AU - Engelborghs, Sebastiaan
AU - Escott-Price, Valentina
AU - Espinosa, Ana
AU - Ewers, Michael
AU - Faber, Kelley M.
AU - Fabrizio, Tagliavini
AU - Nielsen, Sune Fallgaard
AU - Fardo, David W.
AU - Farotti, Lucia
AU - Fenoglio, Chiara
AU - Fernández-Fuertes, Marta
AU - Ferrari, Raffaele
AU - Ferreira, Catarina B.
AU - Ferri, Evelyn
AU - Fin, Bertrand
AU - Fischer, Peter
AU - Fladby, Tormod
AU - Fließbach, Klaus
AU - Fongang, Bernard
AU - Fornage, Myriam
AU - Fortea, Juan
AU - Foroud, Tatiana M.
AU - Fostinelli, Silvia
AU - Fox, Nick C.
AU - Franco-Macías, Emlio
AU - Bullido, María J.
AU - Frank-García, Ana
AU - Froelich, Lutz
AU - Fulton-Howard, Brian
AU - Galimberti, Daniela
AU - García-Alberca, Jose Maria
AU - García-González, Pablo
AU - Garcia-Madrona, Sebastian
AU - Garcia-Ribas, Guillermo
AU - Ghidoni, Roberta
AU - Giegling, Ina
AU - Giorgio, Giaccone
AU - Goate, Alison M.
AU - Goldhardt, Oliver
AU - Gomez-Fonseca, Duber
AU - González-Pérez, Antonio
AU - Graff, Caroline
AU - Grande, Giulia
AU - Green, Emma
AU - Grimmer, Timo
AU - Grünblatt, Edna
AU - Grunin, Michelle
AU - Gudnason, Vilmundur
AU - Guetta-Baranes, Tamar
AU - Haapasalo, Annakaisa
AU - Hadjigeorgiou, Georgios
AU - Haines, Jonathan L.
AU - Hamilton-Nelson, Kara L.
AU - Hampel, Harald
AU - Hanon, Olivier
AU - Hardy, John
AU - Hartmann, Annette M.
AU - Hausner, Lucrezia
AU - Harwood, Janet
AU - Heilmann-Heimbach, Stefanie
AU - Helisalmi, Seppo
AU - Heneka, Michael T.
AU - Hernández, Isabel
AU - Herrmann, Martin J.
AU - Hoffmann, Per
AU - Holmes, Clive
AU - Holstege, Henne
AU - Vilas, Raquel Huerto
AU - Hulsman, Marc
AU - Humphrey, Jack
AU - Biessels, Geert Jan
AU - Jian, Xueqiu
AU - Johansson, Charlotte
AU - Jun, Gyungah R.
AU - Kastumata, Yuriko
AU - Kauwe, John
AU - Kehoe, Patrick G.
AU - Kilander, Lena
AU - Ståhlbom, Anne Kinhult
AU - Kivipelto, Miia
AU - Koivisto, Anne
AU - Kornhuber, Johannes
AU - Kosmidis, Mary H.
AU - Benitez, Bruno A.
AU - Cruchaga, Carlos
AU - Fernandez-Hernandez, Victoria
AU - Harari, Oscar
AU - Ibanez, Laura
AU - Morris, John C.
N1 - Funding Information: We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). 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). Full consortium acknowledgements and funding are in the Supplementary Note. Funding Information: We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). 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). Full consortium acknowledgements and funding are in the . Publisher Copyright: © 2022, The Author(s).
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128487295&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01024-z
DO - 10.1038/s41588-022-01024-z
M3 - Article
C2 - 35379992
AN - SCOPUS:85128487295
SN - 1061-4036
VL - 54
SP - 412
EP - 436
JO - Nature Genetics
JF - Nature Genetics
IS - 4
ER -