Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all...

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Autores: De Rojas, Itziar, EADB contributors, The GR@ACE study group, DEGESCO Consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, López de Munain Arregui, Adolfo José
Formato: artículo
Fecha de publicación:2021
País:España
Recursos:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/52011
Acesso em linha:http://hdl.handle.net/10810/52011
Access Level:acceso abierto
Palavra-chave:alzheimer's disease
polygenetic risk
preventive and curative clinical trials
SHARPIN gene
stratifying by APOE
individuals at high risk
id ES_31cedff8f2f3337b3e87402df52b1ccd
oai_identifier_str oai:addi.ehu.eus:10810/52011
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
title Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
spellingShingle Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
De Rojas, Itziar
alzheimer's disease
polygenetic risk
preventive and curative clinical trials
SHARPIN gene
stratifying by APOE
individuals at high risk
title_short Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
title_full Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
title_fullStr Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
title_full_unstemmed Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
title_sort Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk Scores
dc.creator.none.fl_str_mv De Rojas, Itziar
EADB contributors
The GR@ACE study group
DEGESCO Consortium
IGAP (ADGC, CHARGE, EADI, GERAD)
PGC-ALZ consortia
López de Munain Arregui, Adolfo José
author De Rojas, Itziar
author_facet De Rojas, Itziar
EADB contributors
The GR@ACE study group
DEGESCO Consortium
IGAP (ADGC, CHARGE, EADI, GERAD)
PGC-ALZ consortia
López de Munain Arregui, Adolfo José
author_role author
author2 EADB contributors
The GR@ACE study group
DEGESCO Consortium
IGAP (ADGC, CHARGE, EADI, GERAD)
PGC-ALZ consortia
López de Munain Arregui, Adolfo José
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Commission
dc.subject.none.fl_str_mv alzheimer's disease
polygenetic risk
preventive and curative clinical trials
SHARPIN gene
stratifying by APOE
individuals at high risk
topic alzheimer's disease
polygenetic risk
preventive and curative clinical trials
SHARPIN gene
stratifying by APOE
individuals at high risk
description Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n=409,435 and validation size n=58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/52011
url http://hdl.handle.net/10810/52011
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/EC/H2020/115975
info:eu-repo/grantAgreement/EC/H2020/115985
https://www.nature.com/articles/s41467-021-22491-8
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Common Variants in Alzheimer’s Disease and Risk Stratification by Polygenic Risk ScoresDe Rojas, ItziarEADB contributorsThe GR@ACE study groupDEGESCO ConsortiumIGAP (ADGC, CHARGE, EADI, GERAD)PGC-ALZ consortiaLópez de Munain Arregui, Adolfo Joséalzheimer's diseasepolygenetic riskpreventive and curative clinical trialsSHARPIN genestratifying by APOEindividuals at high riskGenetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n=409,435 and validation size n=58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.The present work has been performed as part of the doctoral program of I. de Rojas at the Universitat de Barcelona (Barcelona, Spain) supported by national grant from the Instituto de Salud Carlos III FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). 100-Plus study. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW project number 733050814, 733050512) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project numb 733051061). Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of LongTerm Care. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND) and also funded by Inserm, Institut Pasteur de Lille, the Lille Métropole Communauté Urbaine, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Genotyping of the German case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND (German Federal Ministry of Education and Research, BMBF: 01ED1619A). The i–Select chips was funded by the French National Foundation on AD and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer’s Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIA/NHLBI grants AG049505, AG058589, HL105756 and AGES contract N01–AG–12100, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association grant ADGC–10–196728SpringerEuropean Commission202120212021info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/52011reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/EC/H2020/115975info:eu-repo/grantAgreement/EC/H2020/115985https://www.nature.com/articles/s41467-021-22491-8info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)oai:addi.ehu.eus:10810/520112026-06-18T09:23:17Z
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