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Exome sequencing identifies novel AD-associated genes.

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, Holger Hummerich, Amit Kawalia, Philippe Amouyel, Gary Beecham, Claudine Berr, Joshua Bis, Anne Boland, Paola Bossu, Femke Bouwman, Dominique Campion, Antonio Daniele, Jean-Francois Dartigues, Stephanie Debette, Jean-Francois Deleuze, Nicola Denning, Anita Destefano, Lindsay Farrer, Nick Fox, Daniela Glimberti, Emmanuelle Genin, Jonathan Haines, Clive Holmes, Mohammad Arfan Ikram, M. Ikram, Iris Jansen, Robert Kraaij, Mark Lathrop, Afina Lemstra, Alberto Lleo, Lauren Luckcuck, Rachel Marschall, Eden Martin, Carlo Masullo, Richard Mayeux, Patrizia Mecocci, Alun Meggy, Merel Mol, Kevin Morgan, Benedetta Nacmia, Adam C Naj, Pau Pastor, Margaret Pericak-Vance, Rachel Raybould, Richard Redon, Anne-Claire Richard, Steffi Riedel-Heller, Fernando Rivadeneira, Stephane Rousseau, Natalie Ryan, Salha Saad, Pascal Sanchez-Juan, Gerald Schellenberg, Philip Scheltens, Jonathan Scott, Davide Seripa, Gianfranco Spalletta, Betty M. Tijms, Andre Uitterlinden, Sven van der Lee, Michael Wagner, David Wallon, Li San Wang, Aline Zarea, Marcel Reinders, Jordi Clarimon, John van Swieten, John Hardy, Alfredo Ramirez, Simon 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

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-{varepsilon}4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

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