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  • Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease
    Holstege, Henne; 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; Martin, Eden R; Masullo, Carlo; Mayeux, Richard; 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; Richard, Anne-Claire; Riedel-Heller, Steffi G; Rivadeneira, Fernando; Rousseau, Stéphane; 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, André G; van der Lee, Sven J; Visser, Pieter Jelle; Wallon, David; Wang, Li-San; 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, Gaël; Bellenguez, Céline; Lambert, Jean-Charles

    Nature genetics, 12/2022, Volume: 54, Issue: 12
    Journal Article

    Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70% . The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants . 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.

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