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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 ?4 allele
Fuente: Nature Genetics, 2022, 54(4), 412-436
Publisher: Nature Publishing Group
Year of publication: 2022
No. of pages: 33
Publication type: Article
DOI: 10.1038/s41588-022-01024-z
ISSN: 1061-4036,1546-1718
Publication Url: https://doi.org/10.1038/s41588-022-01024-z
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BELLENGUEZ, CÉLINE
KÜÇÜKALI, FAHRI
JANSEN, IRIS E.
KLEINEIDAM, LUCA
MORENO-GRAU, SONIA
AMIN, NAJAF
NAJ, ADAM C.
CAMPOS-MARTIN, RAFAEL
GRENIER-BOLEY, BENJAMIN
ANDRADE, VICTOR
HOLMANS, PETER A.
BOLAND, ANNE
DAMOTT, VINCENT
LEE, SVEN J. VAN DER
COSTA, MARCOS R.
KUULAMAA, TEEMU
YANG, QIONG
ROJAS, ITZIAR DE
ELOY MANUEL RODRIGUEZ RODRIGUEZ
BIS, JOSHUA C.
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