Abstract
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.
| Original language | English |
|---|---|
| Article number | 3417 |
| Pages (from-to) | 1-16 |
| Number of pages | 16 |
| Journal | Nature communications |
| Volume | 12 |
| Issue number | 1 |
| Early online date | 7 Jun 2021 |
| DOIs | |
| Publication status | Published - 1 Dec 2021 |
Access to Document
Other files and links
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature communications, Vol. 12, No. 1, 3417, 01.12.2021, p. 1-16.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
AU - EADB contributors
AU - The GR@ACE study group
AU - DEGESCO consortium
AU - IGAP (ADGC, CHARGE, EADI, GERAD)
AU - PGC-ALZ consortia
AU - de Rojas, I.
AU - Moreno-Grau, S.
AU - Tesi, Niccolo
AU - Grenier-Boley, Benjamin
AU - Andrade, Victor
AU - Jansen, Iris E.
AU - Pedersen, Nancy L.
AU - Stringa, Najada
AU - Zettergren, Anna
AU - Hernández, I.
AU - Montrreal, Laura
AU - Antúnez, Carmen
AU - Antonell, Anna
AU - Tankard, Rick M.
AU - Bis, Joshua C.
AU - Sims, Rebecca
AU - Bellenguez, Céline
AU - Quintela, Inés
AU - González-Perez, Antonio
AU - Calero, Miguel
AU - Franco-Macías, Emilio
AU - Macías, Juan
AU - Blesa, Rafael
AU - Cervera-Carles, Laura
AU - Menéndez-González, Manuel
AU - Frank-García, Ana
AU - Royo, Jose Luís
AU - Moreno, Fermin
AU - Huerto Vilas, Raquel
AU - Baquero, Miquel
AU - Diez-Fairen, Mónica
AU - Lage, C.
AU - García-Madrona, Sebastián
AU - García-González, Pablo
AU - Alarcón-Martín, Emilio
AU - Valero, S.
AU - Sotolongo-Grau, Oscar
AU - Ullgren, Abbe
AU - Naj, Adam C.
AU - Lemstra, Afina W.
AU - Benaque, Alba
AU - Pérez-Cordón, Alba
AU - Benussi, Alberto
AU - Rábano, Alberto
AU - Padovani, Alessandro
AU - Squassina, Alessio
AU - de Mendonça, Alexandre
AU - Arias Pastor, Alfonso
AU - Huisman, Martijn
AU - Posthuma, Danielle
AU - Kok, Almar A. L.
N1 - Funding Information: We would like to thank patients and controls who participated in this project. 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”). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. 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: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. 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. Geno-typing 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 number 733051061). Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. 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). Full acknowledgments for the studies that contributed data can be found in the Supplementary Note. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data. We thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. 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–10–196728. This research has been conducted using the UK Biobank public resource obtained through the University of Edinburg Data Share (https://datashare.is.ed.ac.uk/handle/10283/3364). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85107895788&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107895788&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-021-22491-8
DO - https://doi.org/10.1038/s41467-021-22491-8
M3 - Article
C2 - 34099642
SN - 2041-1723
VL - 12
SP - 1
EP - 16
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3417
ER -