Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
Autor: | Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, 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., 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., Marshall, Rachel, Martin, Eden R., Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam C., Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A., Raybould, Rachel, Redon, Richard, Reinders, Marcel J. T., Richard, Anne-Claire, Riedel-Heller, Steffi G., Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S., Saad, Salha, Sánchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A., Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo, Tijms, Betty, Uitterlinden, André G., van der Lee, Sven J., Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimón, Jordi, van Swieten, John C., Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John, Ramirez, Alfredo, Mead, Simon, van der Flier, Wiesje M., van Duijn, Cornelia M., Williams, Julie, Nicolas, Gaël, Bellenguez, Céline, Lambert, Jean-Charles, Universitat Autònoma de Barcelona |
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Přispěvatelé: | Internal Medicine, Neurology, Epidemiology, Amsterdam Neuroscience - Neurodegeneration, VU University medical center, Human genetics, General practice, Amsterdam Neuroscience - Brain Imaging, APH - Personalized Medicine, APH - Methodology, Complex Trait Genetics, Human Genetics, ACS - Pulmonary hypertension & thrombosis |
Rok vydání: | 2022 |
Předmět: |
Adenosine Triphosphatases
rare damaging variants Membrane Transport Proteins genetics [Alzheimer Disease] Alzheimer's disease ATP8B4 protein human genetics [Adenosine Triphosphatases] genetics [Exosomes] Settore MED/26 - NEUROLOGIA SDG 3 - Good Health and Well-being Alzheimer Disease Risk Factors ddc:570 Genetics research ABCA1 protein human Genetics SORL1 protein human Humans genetics [ATP Binding Cassette Transporter 1] LDL-Receptor Related Proteins Genome-Wide Association Study ATP Binding Cassette Transporter 1 |
Zdroj: | Nature genetics 54(12), 1786-1794 (2022). doi:10.1038/s41588-022-01208-7 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 L & Lambert, J-C 2022, ' Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease ', Nature Genetics, vol. 54, no. 12, pp. 1786-1794 . https://doi.org/10.1038/s41588-022-01208-7 Nature Genetics, 54(12), 1786-1794. Nature Publishing Group 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 2022, ' Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease ', Nature genetics, vol. 54, no. 12, pp. 1786-1794 . https://doi.org/10.1038/s41588-022-01208-7 Nature Genetics, 54(12) Nature genetics, 54(12), 1786-1794. Nature Publishing Group Nature Genetics |
ISSN: | 1546-1718 1061-4036 |
Popis: | 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. |
Databáze: | OpenAIRE |
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