New insights into the genetic etiology of Alzheimer?s disease and related dementias

Autores
Bellenguez, Céline; Kucukali, Fahri; Jansen, Iris; Kleineidam, Lucas; Moreno Grau, Sonia; Morelli, Laura; Galeano, Pablo; Novack, Gisela Vanina; Prestia, Federico Ariel; Castaño, Eduardo Miguel; Ruiz, Agustín; Ramirez, Alfredo; Lambert, Jean Charles
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Bellenguez, Céline. Inserm; Francia. Université de Lille; Francia
Fil: Kucukali, Fahri. Center For Molecular Neurology; Bélgica. University of Antwerp; Bélgica
Fil: Jansen, Iris. Vrije Universiteit Amsterdam; Países Bajos
Fil: Kleineidam, Lucas. University Of Cologne; Alemania
Fil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; España
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Novack, Gisela Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Prestia, Federico Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Ruiz, Agustín. Universitat Internacional de Catalunya; España
Fil: Ramirez, Alfredo. University Of Cologne; Alemania
Fil: Lambert, Jean Charles. Inserm; Francia
Materia
Alzheimer’s disease
dementias
genetic
APOE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/218139
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/218139
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling New insights into the genetic etiology of Alzheimer?s disease and related dementiasBellenguez, CélineKucukali, FahriJansen, IrisKleineidam, LucasMoreno Grau, SoniaMorelli, LauraGaleano, PabloNovack, Gisela VaninaPrestia, Federico ArielCastaño, Eduardo MiguelRuiz, AgustínRamirez, AlfredoLambert, Jean CharlesAlzheimer’s diseasedementiasgeneticAPOEhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Characterization 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.Fil: Bellenguez, Céline. Inserm; Francia. Université de Lille; FranciaFil: Kucukali, Fahri. Center For Molecular Neurology; Bélgica. University of Antwerp; BélgicaFil: Jansen, Iris. Vrije Universiteit Amsterdam; Países BajosFil: Kleineidam, Lucas. University Of Cologne; AlemaniaFil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; EspañaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Novack, Gisela Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Prestia, Federico Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ruiz, Agustín. Universitat Internacional de Catalunya; EspañaFil: Ramirez, Alfredo. University Of Cologne; AlemaniaFil: Lambert, Jean Charles. Inserm; FranciaNature Publishing Group2022-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/218139Bellenguez, Céline; Kucukali, Fahri; Jansen, Iris; Kleineidam, Lucas; Moreno Grau, Sonia; et al.; New insights into the genetic etiology of Alzheimer?s disease and related dementias; Nature Publishing Group; Nature Genetics; 54; 4-2022; 412-4361061-4036CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41588-022-01024-zinfo:eu-repo/semantics/altIdentifier/url/https://doi.org/10.1038/s41588-022-01024-zinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:40:47Zoai:ri.conicet.gov.ar:11336/218139instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:40:47.507CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv New insights into the genetic etiology of Alzheimer?s disease and related dementias
title New insights into the genetic etiology of Alzheimer?s disease and related dementias
spellingShingle New insights into the genetic etiology of Alzheimer?s disease and related dementias
Bellenguez, Céline
Alzheimer’s disease
dementias
genetic
APOE
title_short New insights into the genetic etiology of Alzheimer?s disease and related dementias
title_full New insights into the genetic etiology of Alzheimer?s disease and related dementias
title_fullStr New insights into the genetic etiology of Alzheimer?s disease and related dementias
title_full_unstemmed New insights into the genetic etiology of Alzheimer?s disease and related dementias
title_sort New insights into the genetic etiology of Alzheimer?s disease and related dementias
dc.creator.none.fl_str_mv Bellenguez, Céline
Kucukali, Fahri
Jansen, Iris
Kleineidam, Lucas
Moreno Grau, Sonia
Morelli, Laura
Galeano, Pablo
Novack, Gisela Vanina
Prestia, Federico Ariel
Castaño, Eduardo Miguel
Ruiz, Agustín
Ramirez, Alfredo
Lambert, Jean Charles
author Bellenguez, Céline
author_facet Bellenguez, Céline
Kucukali, Fahri
Jansen, Iris
Kleineidam, Lucas
Moreno Grau, Sonia
Morelli, Laura
Galeano, Pablo
Novack, Gisela Vanina
Prestia, Federico Ariel
Castaño, Eduardo Miguel
Ruiz, Agustín
Ramirez, Alfredo
Lambert, Jean Charles
author_role author
author2 Kucukali, Fahri
Jansen, Iris
Kleineidam, Lucas
Moreno Grau, Sonia
Morelli, Laura
Galeano, Pablo
Novack, Gisela Vanina
Prestia, Federico Ariel
Castaño, Eduardo Miguel
Ruiz, Agustín
Ramirez, Alfredo
Lambert, Jean Charles
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer’s disease
dementias
genetic
APOE
topic Alzheimer’s disease
dementias
genetic
APOE
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Bellenguez, Céline. Inserm; Francia. Université de Lille; Francia
Fil: Kucukali, Fahri. Center For Molecular Neurology; Bélgica. University of Antwerp; Bélgica
Fil: Jansen, Iris. Vrije Universiteit Amsterdam; Países Bajos
Fil: Kleineidam, Lucas. University Of Cologne; Alemania
Fil: Moreno Grau, Sonia. Universitat Internacional de Catalunya; España
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Novack, Gisela Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Prestia, Federico Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Castaño, Eduardo Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Ruiz, Agustín. Universitat Internacional de Catalunya; España
Fil: Ramirez, Alfredo. University Of Cologne; Alemania
Fil: Lambert, Jean Charles. Inserm; Francia
description 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.
publishDate 2022
dc.date.none.fl_str_mv 2022-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/218139
Bellenguez, Céline; Kucukali, Fahri; Jansen, Iris; Kleineidam, Lucas; Moreno Grau, Sonia; et al.; New insights into the genetic etiology of Alzheimer?s disease and related dementias; Nature Publishing Group; Nature Genetics; 54; 4-2022; 412-436
1061-4036
CONICET Digital
CONICET
url http://hdl.handle.net/11336/218139
identifier_str_mv Bellenguez, Céline; Kucukali, Fahri; Jansen, Iris; Kleineidam, Lucas; Moreno Grau, Sonia; et al.; New insights into the genetic etiology of Alzheimer?s disease and related dementias; Nature Publishing Group; Nature Genetics; 54; 4-2022; 412-436
1061-4036
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41588-022-01024-z
info:eu-repo/semantics/altIdentifier/url/https://doi.org/10.1038/s41588-022-01024-z
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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