Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

APP protein, human; Amyloid beta-Protein Precursor; Apolipoproteins E; Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease/epidemiology; Alzheimer Disease/genetics; Alzheimer Disease/pathology; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/metabolism; Apolipoproteins E/genetics; Case-Control Studies; Cohort Studies; Datasets as Topic; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Heterozygote; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Assessment/methods; Risk Factors; Multifactorial Inheritance; Alzheimer Disease; Risk Assessment; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary

Abstract :

[en] 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.

Disciplines :

Neurology

Author, co-author :

de Rojas, Itziar ; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain

Moreno-Grau, Sonia; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain

Tesi, Niccolo; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands ; Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands ; Delft Bioinformatics Lab, Delft Univeristy of Technology, Delft, The Netherlands

Grenier-Boley, Benjamin; Univ. Lille, Inserm, Institut Pasteur de Lille, CHU Lille, U1167-Labex DISTALZ-RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France

Andrade, Victor; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany ; Department of Neurodegenerative diseases and Geriatric Psychiatry, University Clinic Bonn, Bonn, Germany

Jansen, Iris E; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands ; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands

Pedersen, Nancy L; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

Stringa, Najada ; Amsterdam UMC-Vrije Universiteit Amsterdam, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands

Zettergren, Anna ; Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AgeCap), University of Gothenburg, Gothenburg, Sweden

Hernández, Isabel; Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain ; CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain

More authors (288 more)

External co-authors :

yes

Language :

English

Title :

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Publication date :

07 June 2021

Journal title :

Nature Communications

eISSN :

2041-1723

Publisher :

Nature Research, England

Volume :

Issue :

Pages :

3417

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.nature.com/articles/s41467-021-22491-8.pdf

Funding text :

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).

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