Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel 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 ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, 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. , Fernandez Maria Victoria , Fox Nick C. , Galimberti Daniela , Genin Emmanuelle , Gille Hans , Guen Yann Le , 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 , Sorbi Sandro , van Spaendonk Resie , Spalletta Gianfranco , Tesi Niccólo , Tijms Betty , Uitterlinden André G , van der Lee Sven J. , de 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: July 2020

The genetic component of Alzheimer’s 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, Aβ-aggregation, lipid metabolism and microglial function in AD.