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

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

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

Holstege, Henne; Hulsman, Marc; Charbonnier, Camille; Grenier-Boley, Benjamin; Quenez, Olivier; Grozeva, Detelina; van Rooij, Jeroen; Sims, Rebecca; Ahmad, Shahzad; Amin, Najaf; Norsworthy, Penny; Dols-Icardo, Oriol; Hummerich, Holger; Kawalia, Amit; Amouyel, Philippe; Beecham, Gary; Berr, Claudine; Bis, Joshua; Boland, Anne; Bossu, Paola; Bouwman, Femke; Bras, Jose; Campion, Dominique; Cochran, Jesse Nicholas; Daniele, Antonio; Dartigues, Jean-Francois; Debette, Stephanie; Deleuze, Jean-Francois; Denning, Nicola; Destefano, Anita; Farrer, Lindsay; Fernandez, Maria-Victoria; Fox, Nick; Galimberti, Daniela; Genin, Emmanuelle; Gille, Johan JP; Le Guen, Yann; Guerreiro, Rita; Haines, Jonathan; Holmes, Clive; Ikram, M. Arfan; Ikram, M. Kamran; Jansen, Iris E.; Kraaij, Robert; Lathrop, Mark; Lemstra, Afina W.; Lleo, Alberto; Luckcuck, Lauren; Mannens, Marcel M.A.M.; Marschall, Rachel; Martin, Eden; Masullo, Carlo; Mayeux, Richard; Mecocci, Patrizia; Meggy, Alun; Mol, Merel; Morgan, Kevin; M...

Authors

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 Mol

KEVIN MORGAN kevin.morgan@nottingham.ac.uk
Professor of Human Genomics and Molecular Genetics

Richard M. Myers

Benedetta Nacmias

Adam Naj

Valerio Napolioni

Florence Pasquier

Pau Pastor

Margaret Pericak-Vance

Rachel Raybould

Richard Redon

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 M. 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 van der Flier

Cornelia van Duijn

Julie Williams

Gael Nicolas

Celine Bellenguez

Jean-Charles Lambert

Abstract

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.

Citation

Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., …Lambert, J. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimers Disease

Deposit Date	Jun 6, 2022
Publicly Available Date	Jun 6, 2022
Public URL	https://nottingham-repository.worktribe.com/output/7352699
Publisher URL	https://www.medrxiv.org/content/10.1101/2020.07.22.20159251v5