Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease
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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-Francois | Debette, Stephanie | Deleuze, Jean-Francois | Denning, Nicola | Destefano, Anita L. | Farrer, Lindsay A. | Fernandez, 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. | Lleo, 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, Stephane | Ryan, Natalie S. | Saad, Salha | Sanchez-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, Andre G. | van der Lee, Sven J. | Visser, Pieter Jelle | Wagner, Michael | Wallon, David | Wang, Li-San | Zarea, Aline | Clarimon, 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, Gael | Bellenguez, Celine | Lambert, Jean-Charles
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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-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
