Print Email Facebook Twitter Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease 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 estimatedheritability 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. To reference this document use: 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 Files PDF s41588_022_01208_7_1.pdf 8.11 MB Close viewer /islandora/object/uuid:1b0fc51e-bfb9-4056-8992-d901301bcf00/datastream/OBJ/view