Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22491-8
Keywords
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Categories
Funding
- Instituto de Salud Carlos III [FI20/00215]
- Grifols SA
- Fundacion bancaria La Caixa
- Fundacio ACE
- CIBERNED
- European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED project [115975]
- European Union/EFPIA Innovative Medicines Initiative Joint undertaking MOPEAD project [115985]
- ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion
- Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa)
- Stichting Alzheimer Nederland
- Stichting VUmc fonds
- Stichting Dioraphte
- JPco-fuND (ZonMW) [733051061]
- Stichting Alzheimer Nederland [WE09.2014-03]
- Stichting Diorapthe
- horstingstuit foundation
- Memorabel (ZonMW) [733050814, 733050512]
- Netherlands Ministry of Health, Welfare and Sports, Directorate of LongTerm Care
- European Alzheimer DNA BioBank, EADB from the EU Joint Program-Neurodegenerative Disease Research (JPND)
- Inserm
- Institut Pasteur de Lille
- Lille Metropole Communaute Urbaine
- French government's LABEX DISTALZ program
- JPco-fuND (German Federal Ministry of Education and Research, BMBF) [01ED1619A]
- French National Foundation
- LABEX (laboratory of excellence program investment for the future)
- Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480]
- Alzheimer's Research UK [503176]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01GI0102, 01GI0711, 01GI0420]
- NIA/NHLBI [AG049505, AG058589, HL105756]
- AGES [N01-AG-12100]
- Icelandic Heart Association
- Erasmus Medical Center and Erasmus University
- NIH/NIA [U01 AG032984, U24 AG021886, U01 AG016976]
- Alzheimer's Association [ADGC-10-196728]
- [PI13/02434]
- [PI16/01861]
- [PI17/01474]
- [PI19/01240]
- [PI19/01301]
- ESRC [ES/G035954/1] Funding Source: UKRI
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This study identified 6 new genetic variants associated with Alzheimer's disease risk through a large-scale genetic association study. It also demonstrated the efficacy of a polygenic risk score in stratifying individuals at high risk of Alzheimer's disease, providing important data support for further research and preventive treatment of the disease.
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 4 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. Known genetic loci account for only a fraction of the genetic contribution to Alzheimer's disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer's disease polygenic risk score.
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