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Nature Research, Nature Genetics, 12(54), p. 1786-1794, 2022

DOI: 10.1038/s41588-022-01208-7



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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Journal article published in 2022 by Henne Holstege ORCID, Marc Hulsman ORCID, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez ORCID, Detelina Grozeva ORCID, Jeroen G. J. van Rooij, Rebecca Sims ORCID, Shahzad Ahmad ORCID, Najaf Amin ORCID, Penny J. Norsworthy ORCID, Oriol Dols-Icardo ORCID, Holger Hummerich, Amit Kawalia, Philippe Amouyel ORCID and other authors.
This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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AbstractAlzheimer’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.