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

Henne Holstege; Marc Hulsman; Camille Charbonnier; Benjamin Grenier-Boley; Olivier Quenez; Detelina Grozeva; 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-Francois Dartigues; Stephanie Debette; Jean-Francois Deleuze; Nicola Denning; Anita L. Destefano; Lindsay A. Farrer; Maria Victoria Fernandez; Nick C. Fox; Daniela Galimberti; Emmanuelle Genin; 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 Lleo; Lauren Luckcuck; Marcel M. A. M. Mannens; Rachel Marshall; Eden R. Martin; Carlo Masullo; Richard Mayeux; Patrizia Mecocci; Alun Meggy; Merel O. Mol; Kevin Morgan; 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; Stephane 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; Andre 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; John Hardy; Alfredo Ramirez; Simon Mead; Wiesje M. van der Flier; Cornelia M. van Duijn; Julie Williams; Gael Nicolas; Celine Bellenguez; Jean-Charles Lambert

doi:10.1038/s41588-022-01208-7

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

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

Henne Holstege, Marc Hulsman, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Detelina Grozeva, Jeroen G. J. van Rooij, Rebecca Sims, Shahzad Ahmad, Najaf Amin, …

Nature Genetics, Vol.54, pp.1786-1794

21/11/2022

DOI: https://doi.org/10.1038/s41588-022-01208-7

Abstract

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 variants(2). 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.

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Title: Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease
Creators - without role: Henne Holstege - Amsterdam University Medical Centers
Marc Hulsman - Amsterdam University Medical Centers
Camille Charbonnier - Inserm
Benjamin Grenier-Boley - Inserm
Olivier Quenez - Inserm
Detelina Grozeva - Cardiff University
Jeroen G. J. van Rooij - Erasmus MC
Rebecca Sims - Cardiff University
Shahzad Ahmad - Centre for Human Drug Research
Najaf Amin - Erasmus University Rotterdam
Penny J. Norsworthy - MRC Prion Unit
Oriol Dols-Icardo - Hospital de Sant Pau
Holger Hummerich - MRC Prion Unit
Amit Kawalia - University Hospital Cologne
Philippe Amouyel - Institut Pasteur de Lille
Gary W. Beecham - University of Miami
Claudine Berr - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Joshua C. Bis - University of Washington
Anne Boland - Commissariat à l'Énergie Atomique et aux Énergies Alternatives
Paola Bossù - Fondazione Santa Lucia
Femke Bouwman - Amsterdam Neuroscience
Jose Bras - Michigan State University
Dominique Campion - Université de Rouen Normandie
J. Nicholas Cochran - HudsonAlpha Institute for Biotechnology
Antonio Daniele
Jean-Francois Dartigues - Bordeaux Population Health
Stephanie Debette - Inserm
Jean-Francois Deleuze - Commissariat à l'Énergie Atomique et aux Énergies Alternatives
Nicola Denning - Cardiff University
Anita L. Destefano
Lindsay A. Farrer - Boston University
Maria Victoria Fernandez - Hope Center for Neurological Disorders
Nick C. Fox - UK Dementia Research Institute
Daniela Galimberti - University of Milan
Emmanuelle Genin - Inserm
Johan J. P. Gille
Yann Le Guen - Stanford University
Rita Guerreiro - Michigan State University
Jonathan L. Haines - Case Western Reserve University
Clive Holmes - University of Southampton
M. Arfan Ikram - Erasmus University Rotterdam
M. Kamran Ikram - Erasmus University Rotterdam
Iris E. Jansen - Amsterdam Neuroscience
Robert Kraaij - Erasmus University Rotterdam
Marc Lathrop - McGill University and Génome Québec Innovation Centre
Afina W. Lemstra - Vrije Universiteit Amsterdam
Alberto Lleo - Hospital de Sant Pau
Lauren Luckcuck - Cardiff University
Marcel M. A. M. Mannens - Amsterdam University Medical Centers
Rachel Marshall
Eden R. Martin - University of Miami
Carlo Masullo - Università Cattolica del Sacro Cuore
Richard Mayeux - Columbia University
Patrizia Mecocci - University of Perugia
Alun Meggy - Cardiff University
Merel O. Mol - Erasmus University Rotterdam
Kevin Morgan - University of Nottingham
Richard M. Myers - HudsonAlpha Institute for Biotechnology
Benedetta Nacmias - Don Carlo Gnocchi Foundation
Adam C. Naj - University of Pennsylvania
Valerio Napolioni - Stanford University
Florence Pasquier - Inserm
Pau Pastor - Mútua Terrassa
Margaret A. Pericak-Vance - University of Miami
Rachel Raybould - Cardiff University
Richard Redon - Inserm
Marcel J. T. Reinders - Delft University of Technology
Anne-Claire Richard
Steffi G. Riedel-Heller - Leipzig University
Fernando Rivadeneira - Erasmus University Rotterdam
Stephane Rousseau - Université de Rouen Normandie
Natalie S. Ryan - UK Dementia Research Institute
Salha Saad - Cardiff University
Pascual Sanchez-Juan - Universidad de Cantabria
Gerard D. Schellenberg - University of Pennsylvania
Philip Scheltens - Vrije Universiteit Amsterdam
Jonathan M. Schott - University College London
Davide Seripa
Sudha Seshadri - Institute for Neurodegenerative Disorders
Daoud Sie - Amsterdam University Medical Centers
Erik A. Sistermans - Amsterdam University Medical Centers
Sandro Sorbi - University of Florence
Resie van Spaendonk - Amsterdam University Medical Centers
Gianfranco Spalletta - Fondazione Santa Lucia
Niccolo’ Tesi
Betty Tijms - Vrije Universiteit Amsterdam
Andre G. Uitterlinden - Erasmus University Rotterdam
Sven J. van der Lee - Vrije Universiteit Amsterdam
Pieter Jelle Visser - Amsterdam University Medical Centers
Michael Wagner - German Center for Neurodegenerative Diseases
David Wallon - Université de Rouen Normandie
Li-San Wang - University of Pennsylvania
Aline Zarea - Inserm
Jordi Clarimon - Biomedical Research Networking Center on Neurodegenerative Diseases
John C. van Swieten - Erasmus University Rotterdam
Michael D. Greicius - Stanford University
Jennifer S. Yokoyama - University Memory and Aging Center
Carlos Cruchaga - Washington University in St. Louis
John Hardy - University College London
Alfredo Ramirez
Simon Mead - MRC Prion Unit
Wiesje M. van der Flier - Amsterdam Neuroscience
Cornelia M. van Duijn - Erasmus University Rotterdam
Julie Williams - Cardiff University
Gael Nicolas - Inserm
Celine Bellenguez - Institut Pasteur de Lille
Jean-Charles Lambert
Publication Details: Nature Genetics, Vol.54, pp.1786-1794
Identifiers: 9941508609311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-03900692