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 - Diehl-Schmid, Janine
AU - Grimmer, Timo
AU - Priller, Josef
N1 - 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 - https://www.scopus.com/pages/publications/85128487295
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 -