Title
Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
Author
Holstege, H. (TU Delft Intelligent Systems; Vrije Universiteit Amsterdam; Netherlands Institute for Neuroscience, Amsterdam)
Hulsman, M.J. (TU Delft Information management; Vrije Universiteit Amsterdam; Netherlands Institute for Neuroscience, Amsterdam)
Charbonnier, Camille (Université Rouen Normandie, Rouen)
Grenier-Boley, Banjamin (Université de Lille)
Quenez, Olivier (Université Rouen Normandie, Rouen)
Grozeva, Detelina (Cardiff University)
van Rooij, Jeroen G.J. (Erasmus MC; Rotterdam Eye Hospital)
Reinders, M.J.T. (TU Delft Pattern Recognition and Bioinformatics)
van der Lee, S.J. (TU Delft Pattern Recognition and Bioinformatics)
Department
Intelligent Systems
Date
2022
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.
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http://resolver.tudelft.nl/uuid:1b0fc51e-bfb9-4056-8992-d901301bcf00
DOI
https://doi.org/10.1038/s41588-022-01208-7
ISSN
1061-4036
Source
Nature Genetics, 54 (12), 1786-1794
Part of collection
Institutional Repository
Document type
journal article
Rights
© 2022 H. Holstege, M.J. Hulsman, Camille Charbonnier, Banjamin Grenier-Boley, Olivier Quenez, Detelina Grozeva, Jeroen G.J. van Rooij, M.J.T. Reinders, S.J. van der Lee, More Authors