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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Holstege, Henne; Hulsman, Marc; Charbonnier, Camille; Grenier-Boley, Benjamin; Quenez, Olivier; Grozeva, Detelina; van Rooij, Jeroen G.J.; 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.; 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.; Mannens, Marcel M.A.M.; Marshall, Rachel; Martin, Eden...


Henne Holstege

Marc Hulsman

Camille Charbonnier

Benjamin Grenier-Boley

Olivier Quenez

Detelina Grozeva

Jeroen G.J. van Rooij

Jeroen G. J. van Rooij

Rebecca Sims

Shahzad Ahmad

Najaf Amin

Penny J. Norsworthy

Oriol Dols-Icardo

Holger Hummerich

Amit Kawalia

Philippe Amouyel

Gary W. Beecham

Claudine Berr

Joshua C. Bis

Anne Boland

Paola Bossù

Femke Bouwman

Jose Bras

Dominique Campion

J. Nicholas Cochran

Antonio Daniele

Jean François Dartigues

Stéphanie Debette

Jean François Deleuze

Nicola Denning

Anita L. DeStefano

Lindsay A. Farrer

Maria Victoria Fernández

Nick C. Fox

Daniela Galimberti

Emmanuelle Genin

Johan J. P. Gille

Johan J.P. Gille

Yann Le Guen

Rita Guerreiro

Jonathan L. Haines

Clive Holmes

M. Arfan Ikram

M. Kamran Ikram

Iris E. Jansen

Robert Kraaij

Marc Lathrop

Afina W. Lemstra

Alberto Lleó

Lauren Luckcuck

Marcel M. A. M. Mannens

Marcel M.A.M. Mannens

Rachel Marshall

Eden R. Martin

Carlo Masullo

Richard Mayeux

Patrizia Mecocci

Alun Meggy

Merel O. Mol

Professor of Human Genomics and Molecular Genetics

Richard M. Myers

Benedetta Nacmias

Adam C. Naj

Valerio Napolioni

Florence Pasquier

Pau Pastor

Margaret A. Pericak-Vance

Rachel Raybould

Richard Redon

Marcel J.T. Reinders

Anne Claire Richard

Steffi G. Riedel-Heller

Fernando Rivadeneira

Stéphane Rousseau

Natalie S. Ryan

Salha Saad

Pascual Sanchez-Juan

Gerard D. Schellenberg

Philip Scheltens

Jonathan M. Schott

Davide Seripa

Sudha Seshadri

Daoud Sie

Erik A. Sistermans

Sandro Sorbi

Resie van Spaendonk

Gianfranco Spalletta

Niccolo’ Tesi

Betty Tijms

André G. Uitterlinden

Sven J. van der Lee

Pieter Jelle Visser

Michael Wagner

David Wallon

Li San Wang

Aline Zarea

Jordi Clarimon

John C. van Swieten

Michael D. Greicius

Jennifer S. Yokoyama

Carlos Cruchaga

Carlos Cruchaga

Carlos Cruchaga

Carlos Cruchaga

Carlos Cruchaga

Carlos Cruchaga

John Hardy

John Hardy

John Hardy

John Hardy

John Hardy

John Hardy

Alfredo Ramirez

Alfredo Ramirez

Alfredo Ramirez

Alfredo Ramirez

Alfredo Ramirez

Alfredo Ramirez

Simon Mead

Wiesje M. van der Flier

Cornelia M. van Duijn

Julie Williams

Gaël Nicolas

Céline Bellenguez

Jean-Charles Lambert


Alzheimer’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 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.


Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., …Lambert, J. (in press). Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease. Nature Genetics,

Journal Article Type Article
Acceptance Date Nov 22, 2022
Online Publication Date Nov 21, 2022
Deposit Date Nov 25, 2022
Publicly Available Date Dec 2, 2022
Journal Nature Genetics
Print ISSN 1061-4036
Electronic ISSN 1546-1718
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Keywords Genetics
Public URL
Publisher URL


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