Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease
Holstege, Henne (Delft Bioinformatics Lab, Delft University of Technology)
Hulsman, Marc (Delft Bioinformatics Lab, Delft University of Technology)
Charbonnier, Camille (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ)
Grenier-Boley, Benjamin (Université Lille, INSERM, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liées au vieillissement)
Quenez, Olivier (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ)
Grozeva, Detelina (Cardiff University. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine)
van Rooij, Jeroen G. J. (Erasmus Medical Centre. Department of Internal Medicine)
Sims, Rebecca (Cardiff University. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine)
Ahmad, Shahzad (Leiden Academic Centre for Drug Research)
Amin, Najaf (Nuffield Department of Population Health Oxford University)
Norsworthy, Penny J. (Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases)
Dols Icardo, Oriol (Institut d'Investigació Biomèdica Sant Pau)
Hummerich, Holger (Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases)
Kawalia, Amit (Faculty of Medicine and University Hospital Cologne, University of Cologne. Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy)
Amouyel, Philippe (Université Lille, INSERM, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liées au vieillissement)
Beecham, Gary W. (The John P. Hussman Institute for Human Genomics, University of Miami)
Berr, Claudine (Université Montpellier, INSERM, Institute for Neurosciences of Montpellier)
Bis, Joshua C. (University of Washington. Cardiovascular Health Research Unit, Department of Medicine)
Boland, Anne (Université Paris-Saclay. Centre National de Recherche en Génomique Humaine)
Bossù, Paola (Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation. Experimental Neuro-psychobiology Laboratory, Department of Clinical and Behavioral Neurology)
Bouwman, Femke (Amsterdam Neuroscience, Neurodegeneration)
Bras, Jose (Michigan State University College of Human Medicine. Division of Psychiatry and Behavioral Medicine)
Campion, Dominique (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ)
Cochran, J. Nicholas (HudsonAlpha Institute for Biotechnology)
Daniele, Antonio (Catholic University of Sacred Heart, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico. Department of Neuroscience)
Dartigues, Jean-François (Université Bordeaux, INSERM, Bordeaux Population Health Research Center)
Debette, Stéphanie (Bordeaux University Hospital. Department of Neurology)
Deleuze, Jean-François (Université Paris-Saclay. Centre National de Recherche en Génomique Humaine)
Denning, Nicola (Cardiff University. UKDRI Cardiff, School of Medicine)
DeStefano, Anita L. (Boston University School of Medicine. Department of Neurology)
Farrer, Lindsay A. (Boston University. Department of Medicine (Biomedical Genetics))
Fernández, Maria Victoria (Washington University School of Medicine. Hope Center for Neurological Disorders)
Fox, Nick C. (University College London Queen Square Institute of Neurology. Dementia Research Centre)
Galimberti, Daniela (University of Milan)
Genin, Emmanuelle (Université Brest, INSERM, Etablissement Français du Sang, Centre Hospitalier Universitaire Brest, Unité Mixte de Recherche 1078, GGB, Brest, France)
Gille, Johan J. P. (VU University, AmsterdamUMC (location VUmc). Genome Diagnostics, Department of Human Genetics)
Le Guen, Yann (Stanford University. Department of Neurology and Neurological Sciences)
Guerreiro, Rita (Michigan State University College of Human Medicine. Division of Psychiatry and Behavioral Medicine)
Haines, Jonathan L. (Case Western Reserve University. Department of Epidemiology and Biostatistics)
Holmes, Clive (University of Southampton. Clinical and Experimental Science, Faculty of Medicine)
Ikram, M. Arfan (Erasmus Medical Centre. Department of Epidemiology)
Ikram, M. Kamran (Erasmus Medical Centre. Department of Epidemiology)
Jansen, Iris E. (Vrije University. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience)
Kraaij, Robert (Erasmus Medical Centre. Department of Internal Medicine)
Lathrop, Marc (McGill University and Genome Quebec Innovation Centre)
Lemstra, Afina W. (Amsterdam Neuroscience, Neurodegeneration)
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Luckcuck, Lauren (Cardiff University. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics)
Mannens, Marcel M. A. M. (University of Amsterdam, Amsterdam Reproduction and Development Research Institute. Department of Human Genetics, Amsterdam UMC)
Marshall, Rachel (Cardiff University. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine)
Martin, Eden R. (University of Miami. Dr. John T. Macdonald Foundation Department of Human Genetics)
Masullo, Carlo (Institute of Neurology, Catholic University of the Sacred Heart)
Mayeux, Richard (Columbia University. Gertrude H. Sergievsky Center)
Mecocci, Patrizia (University of Perugia. Institute of Gerontology and Geriatrics, Department of Medicine and Surgery)
Meggy, Alun (Cardiff University. UKDRI Cardiff, School of Medicine)
Mol, Merel O. (Erasmus Medical Centre. Department of Neurology)
Morgan, Kevin (University of Nottingham. Human Genetics, School of Life Sciences)
Myers, Richard M. (HudsonAlpha Institute for Biotechnology)
Nacmias, Benedetta (IRCCS Fondazione Don Carlo Gnocchi)
Naj, Adam C. (University of Pennsylvania Perelman School of Medicine. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine)
Napolioni, Valerio (Genomic and Molecular Epidemiology Laboratory, School of Biosciences and Veterinary Medicine, University of Camerino)
Pasquier, Florence (Université Lille, INSERM, Centre Hospitalier Universitaire Lille, UMR1172, Resources and Research Memory Center (MRRC) of Distalz, Licend)
Pastor, Pau (Hospital Universitari MútuaTerrassa (Terrassa, Catalunya))
Pericak-Vance, Margaret A. (University of Miami. Dr. John T. Macdonald Foundation Department of Human Genetics)
Raybould, Rachel (Cardiff University. UKDRI Cardiff, School of Medicine)
Redon, Richard (Université de Nantes, Centre Hospitalier Universitaire Nantes, Centre National de la Recherche Scientifique, INSERM, l'institut du Thorax)
Reinders, Marcel J. T. (Delft Bioinformatics Lab, Delft University of Technology)
Richard, Anne-Claire (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ)
Riedel-Heller, Steffi G. (Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig)
Rivadeneira, Fernando (Erasmus Medical Centre. Department of Internal Medicine)
Rousseau, Stéphane (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ)
Ryan, Natalie S. (University College London Queen Square Institute of Neurology. Dementia Research Centre)
Saad, Salha (Cardiff University. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine)
Sánchez-Juan, Pascual (Instituto de Investigación Sanitaria Valdecilla (Santander, Cantàbria))
Schellenberg, Gerard D. (University of Pennsylvania Perelman School of Medicine. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine)
Scheltens, Philip (Amsterdam Neuroscience, Neurodegeneration)
Schott, Jonathan M. (University College London Queen Square Institute of Neurology. Dementia Research Centre)
Seripa, Davide (Laboratory for Advanced Hematological Diagnostics, Department of Hematology and Stem Cell Transplant, Lecce, Italy)
Seshadri, Sudha (Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX USA)
Sie, Daoud (VU University, AmsterdamUMC (location VUmc). Genome Diagnostics, Department of Human Genetics)
Sistermans, Erik A. (VU University, AmsterdamUMC (location VUmc). Genome Diagnostics, Department of Human Genetics)
Sorbi, Sandro (IRCCS Fondazione Don Carlo Gnocchi)
van Spaendonk, Resie (VU University, AmsterdamUMC (location VUmc). Genome Diagnostics, Department of Human Genetics)
Spalletta, Gianfranco (Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation. Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology)
Tesi, Niccolo (Delft Bioinformatics Lab, Delft University of Technology)
Tijms, Betty (Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc. Alzheimer Center Amsterdam, Neurology)
Uitterlinden, André G. (Erasmus Medical Centre. Department of Internal Medicine)
van der Lee, Sven J. (Delft Bioinformatics Lab, Delft University of Technology)
Visser, Pieter Jelle (Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc. Alzheimer Center Amsterdam, Neurology)
Wagner, Michael (German Center for Neurodegenerative Diseases)
Wallon, David (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Neurology and CNRMAJ)
Wang, Li-San (University of Pennsylvania Perelman School of Medicine. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine)
Zarea, Aline (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Neurology and CNRMAJ)
Clarimón, Jordi (Institut d'Investigació Biomèdica Sant Pau)
van Swieten, John C. (Erasmus Medical Centre. Department of Neurology)
Greicius, Michael D. (Stanford University. Department of Neurology and Neurological Sciences)
Yokoyama, Jennifer S. (University of California. Memory and Aging Center, Department of Neurology)
Cruchaga, Carlos (Washington University School of Medicine. Hope Center for Neurological Disorders)
Hardy, John (University College London Institute of Neurology. Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience)
Ramirez, Alfredo (University of Cologne. Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases)
Mead, Simon (University College London. Institute of Prion Diseases)
van der Flier, Wiesje M. (Amsterdam Neuroscience, Neurodegeneration)
van Duijn, Cornelia M. (Nuffield Department of Population Health Oxford University)
Williams, Julie (Cardiff University. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine)
Nicolas, Gaël (Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ)
Bellenguez, Céline (Université Lille, INSERM, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liées au vieillissement)
Lambert, Jean-Charles (Université Lille, INSERM, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liées au vieillissement)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70% . The genetic component of AD has been mainly assessed using genome-wide association studies, 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. 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. Multistage gene burden analysis in exome sequencing data from 32,558 individuals identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Genetics research ; Alzheimer's disease
Published in:	Nature genetics, Vol. 54 (november 2022) , p. 1786-1794, ISSN 1546-1718

DOI: 10.1038/s41588-022-01208-7
PMID: 36411364

23 p, 7.9 MB

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