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

tau Proteins; Genome-Wide Association Study; Humans; tau Proteins/genetics; Alzheimer Disease/genetics; Alzheimer Disease/pathology; Cognitive Dysfunction/psychology; Alzheimer Disease; Cognitive Dysfunction; Genetics

Abstract :

[en] 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.

Disciplines :

Neurology

Author, co-author :

Bellenguez, Céline ; Université de Lille, INSERM, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France. celine.bellenguez@pasteur-lille.fr

Küçükali, Fahri ; Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium ; Laboratory of Neurogenetics, Institute Born - Bunge, Antwerp, Belgium ; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

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, Vrije University, Amsterdam, the Netherlands

Kleineidam, Luca; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany ; German Center for Neurodegenerative Diseases (DZNE Bonn), Bonn, Germany

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

Amin, Najaf ; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands ; Nuffield Department of Population Health, Oxford University, Oxford, UK

Naj, Adam C; Department of Biostatistics, Epidemiology, and Informatics, Penn Neurodegeneration Genomics Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA ; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

Campos-Martin, Rafael; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, Cologne, Germany

Grenier-Boley, Benjamin; Université de Lille, INSERM, CHU Lille, Institut Pasteur Lille, U1167-RID-AGE, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France

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

More authors (402 more)

External co-authors :

yes

Language :

English

Title :

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

Publication date :

April 2022

Journal title :

Nature Genetics

ISSN :

1061-4036

eISSN :

1546-1718

Publisher :

Nature Research, United States

Volume :

Issue :

Pages :

412 - 436

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.nature.com/articles/s41588-022-01024-z.pdf

Funding text :

We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Note.We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the .

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