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

Holstege, Henne; Hulsman, Marc; Charbonnier, Camille; Grenier-Boley, Benjamin; Quenez, Olivier; Grozeva, Detelina; van Rooij, Jeroen G.J.; van Rooij, Jeroen G. J.; Sims, Rebecca; Ahmad, Shahzad; Amin, Najaf; Norsworthy, Penny J.; Dols-Icardo, Oriol; Hummerich, Holger; Kawalia, Amit; Amouyel, Philippe; Beecham, Gary W.; Berr, Claudine; Bis, Joshua C.; Boland, Anne; Bossù, Paola; Bouwman, Femke; Bras, Jose; Campion, Dominique; Cochran, J. Nicholas; Daniele, Antonio; Dartigues, Jean François; Debette, Stéphanie; Deleuze, Jean François; Denning, Nicola; DeStefano, Anita L.; Farrer, Lindsay A.; Fernández, Maria Victoria; Fox, Nick C.; Galimberti, Daniela; Genin, Emmanuelle; Gille, Johan J. P.; Gille, Johan J.P.; Le Guen, Yann; Guerreiro, Rita; Haines, Jonathan L.; Holmes, Clive; Ikram, M. Arfan; Ikram, M. Kamran; Jansen, Iris E.; Kraaij, Robert; Lathrop, Marc; Lemstra, Afina W.; Lleó, Alberto; Luckcuck, Lauren; Mannens, Marcel M. A. M.; Mannens, Marcel M.A.M.; Marshall, Rachel; Martin, Eden...

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.

Citation

Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., …Lambert, J. (in press). Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nature Genetics, https://doi.org/10.1038/s41588-022-01208-7

• Journal Article Type: Article
• Acceptance Date: Nov 22, 2022
• Online Publication Date: Nov 21, 2022
• Deposit Date: Nov 25, 2022
• Publicly Available Date: Dec 2, 2022
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/s41588-022-01208-7
• Keywords: Genetics
• Public URL: https://nottingham-repository.worktribe.com/output/14040670
• Publisher URL: https://www.nature.com/articles/s41588-022-01208-7