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 |
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| Authors: | 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.; 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.; 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.; Mead, S.; van der Flier, W.M.; van Duijn, C.M.; Williams, J.; Nicolas, G.; Bellenguez, C.; Lambert, J.-C. |
| Source: | 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, .... |
| Publication Year: | 2022 |
| Subject Terms: | /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being |
| Description: | © 2022, The Author(s).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. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| ISSN: | 1061-4036; 1546-1718 |
| Relation: | info:eu-repo/semantics/altIdentifier/hdl/https://hdl.handle.net/1871.1/36b94cfe-6175-473e-a55e-0b90c14cd543; info:eu-repo/semantics/altIdentifier/pissn/1061-4036; info:eu-repo/semantics/altIdentifier/eissn/1546-1718 |
| DOI: | 10.1038/s41588-022-01208-7 |
| Availability: | https://research.vu.nl/en/publications/36b94cfe-6175-473e-a55e-0b90c14cd543; https://doi.org/10.1038/s41588-022-01208-7; https://hdl.handle.net/1871.1/36b94cfe-6175-473e-a55e-0b90c14cd543; https://www.scopus.com/pages/publications/85142346472; https://www.scopus.com/pages/publications/85142346472#tab=citedBy |
| Rights: | info:eu-repo/semantics/openAccess |
| Accession Number: | edsbas.ECD4488A |
| Database: | BASE |