Henne Holstege
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
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
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.-C. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimers Disease
Working Paper Type | Working Paper |
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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 |
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Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease
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