Journal Article

DZNE-2022-01745

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Holstege, H. ; Hulsman, M. ; Charbonnier, C. ; Grenier-Boley, B. ; Quenez, O. ; Grozeva, D. ; van Rooij, J. G. J. ; Sims, R. ; Ahmad, S. ; Amin, N. ; Norsworthy, P. J. ; Dols-Icardo, O. ; Hummerich, H. ; Kawalia, A. ; Amouyel, P. ; Beecham, G. W. ; Berr, C. ; Bis, J. C. ; Boland, A. ; Bossù, P. ; Bouwman, F. ; Bras, J. ; Campion, D. ; Cochran, J. N. ; Daniele, A. ; Dartigues, J.-F. ; Debette, S. ; Deleuze, J.-F. ; Denning, N. ; DeStefano, A. L. ; Farrer, L. A. ; Fernández, M. V. ; Fox, N. C. ; Galimberti, D. ; Genin, E. ; Gille, J. J. P. ; Le Guen, Y. ; Guerreiro, R. ; Haines, J. L. ; Holmes, C. ; Ikram, M. A. ; Ikram, M. K. ; Jansen, I. E.Extern* ; Kraaij, R. ; Lathrop, M. ; Lemstra, A. W. ; Lleó, A. ; Luckcuck, L. ; Mannens, M. M. A. M. ; Marshall, R. ; Martin, E. R. ; Masullo, C. ; Mayeux, R. ; Mecocci, P. ; Meggy, A. ; Mol, M. O. ; Morgan, K. ; Myers, R. M. ; Nacmias, B. ; Naj, A. C. ; Napolioni, V. ; Pasquier, F. ; Pastor, P. ; Pericak-Vance, M. A. ; Raybould, R. ; Redon, R. ; Reinders, M. J. T. ; Richard, A.-C. ; Riedel-Heller, S. G. ; Rivadeneira, F. ; Rousseau, S. ; Ryan, N. S. ; Saad, S. ; Sanchez-Juan, P. ; Schellenberg, G. D. ; Scheltens, P. ; Schott, J. M. ; Seripa, D. ; Seshadri, S. ; Sie, D. ; Sistermans, E. A. ; Sorbi, S. ; van Spaendonk, R. ; Spalletta, G. ; Tesi, N. ; Tijms, B. ; Uitterlinden, A. G. ; van der Lee, S. J. ; Visser, P. J. ; Wagner, M.Extern* ; Wallon, D. ; Wang, L.-S. ; Zarea, A. ; Clarimon, J. ; van Swieten, J. C. ; Greicius, M. D. ; Yokoyama, J. S. ; Cruchaga, C. ; Hardy, J. ; Ramirez, A.DZNE* ; Mead, S. ; van der Flier, W. M. ; van Duijn, C. M. ; Williams, J. ; Nicolas, G. ; Bellenguez, C. ; Lambert, J.-C.

2022
Macmillan Publishers Limited, part of Springer Nature London

This record in other databases:    

Please use a persistent id in citations: doi:10.1038/s41588-022-01208-7

Abstract: Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Keyword(s): Humans (MeSH) ; Adenosine Triphosphatases: genetics (MeSH) ; Alzheimer Disease: genetics (MeSH) ; ATP Binding Cassette Transporter 1: genetics (MeSH) ; Genome-Wide Association Study (MeSH) ; Risk Factors (MeSH) ; Exosomes: genetics (MeSH) ; ABCA1 protein, human ; Adenosine Triphosphatases ; ATP Binding Cassette Transporter 1 ; ATP8B4 protein, human ; SORL1 protein, human

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Contributing Institute(s):

1. Patient studies (Patient studies, Bonn)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 40 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dataset Holstege, H. ; Hulsman, M. ; Charbonnier, C. ; et al
Dataset: Summary statistics for 'Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's Disease'
Zenodo (2022) [10.5281/zenodo.6818051]2022 BibTeX | EndNote: XML, Text | RIS

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