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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimers Disease

By Henne Holstege, Marc Hulsman, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Detelina Grozeva, Jeroen van Rooij, Rebecca Sims, Shahzad Ahmad, Najaf Amin, Penny Norsworthy, Oriol Dols-Icardo, Holger Hummerich, Amit Kawalia, Philippe Amouyel, Gary Beecham, Claudine Berr, Joshua Bis, Anne Boland, Paola Bossu, Femke Bouwman, Jose Bras, Dominique Campion, Jesse Nicholas Cochran, Antonio Daniele, Jean-Francois Dartigues, Stephanie Debette, Jean-Francois Deleuze, Nicola Denning, Anita Destefano, Lindsay Farrer, Maria-Victoria Fernandez, Nick Fox, Daniela Galimberti, Emmanuelle Genin, Johan JP Gille, Yann Le Guen, Rita Guerreiro, Jonathan Haines, Clive Holmes, M. Arfan Ikram, M Kamran Ikram, Iris E. Jansen, Robert Kraaij, Mark Lathrop, Afina W. Lemstra, Alberto Lleo, Lauren Luckcuck, Marcel M.A.M. Mannens, Rachel Marschall, Eden Martin, Carlo Masullo, Richard Mayeux, Patrizia Mecocci, Alun Meggy, Merel O. Mol, Kevin Morgan, Richard M. Myers, Benedetta Nacmias, Adam Naj, Valerio Napolioni, Florence Pasquier, Pau Pastor, Margaret Pericak-Vance, Rachel Raybould, Jean-Fran├žois Deleuze, Marcel J.T. Reinders, Anne-Claire Richard, Steffi Riedel-Heller, Fernando Rivadeneira, Stephane Rousseau, Natalie Ryan, Salha Saad, Pascual Sanchez-Juan, Gerard Schellenberg, Philip Scheltens, Jonathan Schott, Davide Seripa, Sudha Seshadri, Daoud Sie, Erik A Sistermans, Sandro Sorbi, Resie van Spaendonk, Gianfranco Spalletta, Niccolo Tesi, Betty Tijms, Andre Uitterlinden, Sven van der Lee, Michael Wagner, David Wallon, Li San Wang, Aline Zarea, Jordi Clarimon, John van Swieten, Michael D. Greicius, Jennifer S. Yokoyama, Carlos Cruchaga, John Hardy, Alfredo Ramirez, Simon H Mead, Wiesje M. van der Flier, Cornelia van Duijn, Julie Williams, Gael Nicolas, Celine Bellenguez, Jean-Charles Lambert

Posted 24 Jul 2020
medRxiv DOI: 10.1101/2020.07.22.20159251

The genetic component of Alzheimers disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), 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- in a two-stage analysis. Next to known genes 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. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, A{beta}-aggregation, lipid metabolism and microglial function in AD.

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