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 variants(2). 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-beta precursor protein processing, amyloid-beta aggregation, lipid metabolism and microglial function in AD.
Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease / H. Holstege, M. Hulsman, C. Charbonnier, B. Grenier-Boley, O. Quenez, D. Grozeva, J.G.J. van Rooij, R. Sims, S. Ahmad, N. Amin, P.J. Norsworthy, O. Dols-Icardo, H. Hummerich, A. Kawalia, P. Amouyel, G.W. Beecham, C. Berr, J.C. Bis, A. Boland, P. Bossù, F. Bouwman, J. Bras, D. Campion, J.N. Cochran, A. Daniele, J. Dartigues, S. Debette, J. Deleuze, N. Denning, A.L. Destefano, L.A. Farrer, M.V. Fernández, N.C. Fox, D. Galimberti, E. Genin, J.J.P. Gille, Y. Le Guen, R. Guerreiro, J.L. Haines, C. Holmes, M.A. Ikram, M.K. Ikram, I.E. Jansen, R. Kraaij, M. Lathrop, A.W. Lemstra, A. Lleó, L. Luckcuck, M.M.A.M. Mannens, R. Marshall, E.R. Martin, C. Masullo, R. Mayeux, P. Mecocci, A. Meggy, M.O. Mol, K. Morgan, R.M. Myers, B. Nacmias, A.C. Naj, V. Napolioni, F. Pasquier, P. Pastor, M.A. Pericak-Vance, R. Raybould, R. Redon, M.J.T. Reinders, A. Richard, S.G. Riedel-Heller, F. Rivadeneira, S. Rousseau, N.S. Ryan, S. Saad, P. Sanchez-Juan, G.D. Schellenberg, P. Scheltens, J.M. Schott, D. Seripa, S. Seshadri, D. Sie, E.A. Sistermans, S. Sorbi, R. van Spaendonk, G. Spalletta, N. Tesi, B. Tijms, A.G. Uitterlinden, S.J. van der Lee, P.J. Visser, M. Wagner, D. Wallon, L. Wang, A. Zarea, J. Clarimon, J.C. van Swieten, M.D. Greicius, J.S. Yokoyama, C. Cruchaga, J. Hardy, A. Ramirez, S. Mead, W.M. van der Flier, C.M. van Duijn, J. Williams, G. Nicolas, C. Bellenguez, J. Lambert. - In: NATURE GENETICS. - ISSN 1061-4036. - 54:12(2022 Dec), pp. 1786-1794. [10.1038/s41588-022-01208-7]
Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease
D. GalimbertiMembro del Collaboration Group
;
2022
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 variants(2). 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-beta precursor protein processing, amyloid-beta aggregation, lipid metabolism and microglial function in AD.
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