Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
Authors: 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-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. , 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 Stéphane , 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 André 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 Gaël , Bellenguez Céline , Lambert Jean-Charles 
Published: November 2022

AbstractAlzheimer’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 variants2. 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 inTREM2,SORL1andABCA7, we observed a significant association of rare, predicted damaging variants inATP8B4andABCA1with AD risk, and a suggestive signal inADAM10. Additionally, the rare-variant burden inRIN3, CLU, ZCWPW1andACEhighlighted 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.