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Arfan, de Mendonca, Alexandre, Hort, Jakub ORCID: 0000-0002-1080-3726, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-Francois, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustin, Ramirez, Alfredo ORCID: 0000-0003-4991-763X and Lambert, Jean-Charles (2022). New insights into the genetic etiology of Alzheimer's disease and related dementias. Nature Genet., 54 (4). S. 412 - 441. BERLIN: NATURE PORTFOLIO. ISSN 1546-1718

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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 epsilon 4 allele. Meta-analysis of genome-wide association studies on Alzheimer's disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer's disease and dementia.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
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Ma, YiyiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Martin, Eden R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martin Montes, AngelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinez Rodriguez, CarmenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masullo, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayeux, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mead, SimonUNSPECIFIEDorcid.org/0000-0002-4326-1468UNSPECIFIED
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Medina, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meggy, AlunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehrabian, ShimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Menendez-Gonzalez, ManuelUNSPECIFIEDorcid.org/0000-0002-5218-0774UNSPECIFIED
Mir, PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moebus, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mol, MerelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Molina-Porcel, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montrreal, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morelli, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreno, FerminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, KevinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mosley, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Papenberg, GoranUNSPECIFIEDorcid.org/0000-0003-0279-1988UNSPECIFIED
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Pasquier, FlorenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Pinol-Ripoll, GerardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pisanu, LaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polak, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Ramakers, InezUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Reyes-Dumeyer, DollyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ridge, PerryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel-Heller, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Rosas Allende, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Wang, Li-SanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, RuiqiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Zare, HabilUNSPECIFIEDorcid.org/0000-0001-5902-6238UNSPECIFIED
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Zhu, CongcongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zulaica, MirenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrer, Lindsay A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Psaty, Bruce M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghanbari, MohsenUNSPECIFIEDorcid.org/0000-0002-9476-7143UNSPECIFIED
Raj, TowfiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sachdev, PerminderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mather, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jessen, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ikram, M. ArfanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Mendonca, AlexandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hort, JakubUNSPECIFIEDorcid.org/0000-0002-1080-3726UNSPECIFIED
Tsolaki, MagdaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pericak-Vance, Margaret A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amouyel, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Williams, JulieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frikke-Schmidt, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clarimon, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deleuze, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossi, GiacominaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seshadri, SudhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andreassen, Ole A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ingelsson, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hiltunen, MikkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sleegers, KristelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schellenberg, Gerard D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Duijn, Cornelia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sims, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Flier, Wiesje M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruiz, AgustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Lambert, Jean-CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-699726
DOI: 10.1038/s41588-022-01024-z
Journal or Publication Title: Nature Genet.
Volume: 54
Number: 4
Page Range: S. 412 - 441
Date: 2022
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; NECROSIS-FACTOR-ALPHA; RISK LOCI; PREDICTION MODELS; AMYLOID-BETA; METAANALYSIS; VARIANTS; GENERATION; IMPUTATION; RESPONSESMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69972

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