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


Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
12 2022
Historique:
received: 31 07 2021
accepted: 19 09 2022
pubmed: 22 11 2022
medline: 15 12 2022
entrez: 21 11 2022
Statut: ppublish

Résumé

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%

Identifiants

pubmed: 36411364
doi: 10.1038/s41588-022-01208-7
pii: 10.1038/s41588-022-01208-7
pmc: PMC9729101
doi:

Substances chimiques

ABCA1 protein, human 0
Adenosine Triphosphatases EC 3.6.1.-
ATP Binding Cassette Transporter 1 0
ATP8B4 protein, human EC 3.6.1.-
SORL1 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1786-1794

Subventions

Organisme : NIA NIH HHS
ID : U24 AG021886
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00024/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : U24 AG056270
Pays : United States
Organisme : Medical Research Council
ID : G0701075
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0901254
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R00 AG068271
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : Medical Research Council
ID : MR/N026004/1
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2022. The Author(s).

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Auteurs

Henne Holstege (H)

Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands. h.holstege@amsterdamumc.nl.
Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands. h.holstege@amsterdamumc.nl.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands. h.holstege@amsterdamumc.nl.
Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands. h.holstege@amsterdamumc.nl.

Marc Hulsman (M)

Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands. m.hulsman1@amsterdamumc.nl.
Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands. m.hulsman1@amsterdamumc.nl.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands. m.hulsman1@amsterdamumc.nl.
Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands. m.hulsman1@amsterdamumc.nl.

Camille Charbonnier (C)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France.

Benjamin Grenier-Boley (B)

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, Lille, France.

Olivier Quenez (O)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France.

Detelina Grozeva (D)

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.

Jeroen G J van Rooij (JGJ)

Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands.

Rebecca Sims (R)

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.

Shahzad Ahmad (S)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Leiden Academic Centre for Drug Research, Leiden, the Netherlands.

Najaf Amin (N)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Nuffield Department of Population Health Oxford University, Oxford, UK.

Penny J Norsworthy (PJ)

Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases, London, UK.

Oriol Dols-Icardo (O)

Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.

Holger Hummerich (H)

Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases, London, UK.

Amit Kawalia (A)

Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Philippe Amouyel (P)

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, Lille, France.

Gary W Beecham (GW)

The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.

Claudine Berr (C)

Université Montpellier, INSERM, Institute for Neurosciences of Montpellier, Montpellier, France.

Joshua C Bis (JC)

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.

Anne Boland (A)

Université Paris-Saclay, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de Recherche en Génomique Humaine Evry, Gif-sur-Yvette, France.

Paola Bossù (P)

Experimental Neuro-psychobiology Laboratory, Department of Clinical and Behavioral Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy.

Femke Bouwman (F)

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.

Jose Bras (J)

Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.

Dominique Campion (D)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France.

J Nicholas Cochran (JN)

HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

Antonio Daniele (A)

Department of Neuroscience, Catholic University of Sacred Heart, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

Jean-François Dartigues (JF)

Université Bordeaux, INSERM, Bordeaux Population Health Research Center, Bordeaux, France.

Stéphanie Debette (S)

Université Bordeaux, INSERM, Bordeaux Population Health Research Center, Bordeaux, France.
Department of Neurology, Bordeaux University Hospital, Bordeaux, France.

Jean-François Deleuze (JF)

Université Paris-Saclay, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de Recherche en Génomique Humaine Evry, Gif-sur-Yvette, France.

Nicola Denning (N)

UKDRI Cardiff, School of Medicine, Cardiff University, Cardiff, UK.

Anita L DeStefano (AL)

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Framingham Heart Study, Framingham, MA, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Lindsay A Farrer (LA)

Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Department of Epidemiology, Boston University, Boston, MA, USA.
Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, USA.

Maria Victoria Fernández (MV)

Neurogenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.
Psychiatry Department, Washington University School of Medicine, St Louis, MO, USA.
Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA.

Nick C Fox (NC)

Dementia Research Centre, University College London Queen Square Institute of Neurology, London, UK.

Daniela Galimberti (D)

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Policlinico, Milan, Italy.
University of Milan, Milan, Italy.

Emmanuelle Genin (E)

Université Brest, INSERM, Etablissement Français du Sang, Centre Hospitalier Universitaire Brest, Unité Mixte de Recherche 1078, GGB, Brest, France.

Johan J P Gille (JJP)

Genome Diagnostics, Department of Human Genetics, VU University, AmsterdamUMC (location VUmc), Amsterdam, the Netherlands.

Yann Le Guen (Y)

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.

Rita Guerreiro (R)

Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.

Jonathan L Haines (JL)

Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.

Clive Holmes (C)

Clinical and Experimental Science, Faculty of Medicine, University of Southampton, Southampton, UK.

M Arfan Ikram (MA)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.

M Kamran Ikram (MK)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.

Iris E Jansen (IE)

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, Amsterdam, the Netherlands.

Robert Kraaij (R)

Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands.

Marc Lathrop (M)

McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.

Afina W Lemstra (AW)

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.

Alberto Lleó (A)

Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.

Lauren Luckcuck (L)

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.

Marcel M A M Mannens (MMAM)

Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands.

Rachel Marshall (R)

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.

Eden R Martin (ER)

The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.

Carlo Masullo (C)

Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy.

Richard Mayeux (R)

Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA.
Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.

Patrizia Mecocci (P)

Institute of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

Alun Meggy (A)

UKDRI Cardiff, School of Medicine, Cardiff University, Cardiff, UK.

Merel O Mol (MO)

Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.

Kevin Morgan (K)

Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, UK.

Richard M Myers (RM)

HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

Benedetta Nacmias (B)

Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence, Italy.
IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Adam C Naj (AC)

Penn Neurodegeneration Genomics Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Valerio Napolioni (V)

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Genomic and Molecular Epidemiology Laboratory, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.

Florence Pasquier (F)

Université Lille, INSERM, Centre Hospitalier Universitaire Lille, UMR1172, Resources and Research Memory Center (MRRC) of Distalz, Licend, Lille, France.

Pau Pastor (P)

Fundació Docència i Recerca MútuaTerrassa and Movement Disorders Unit, Department of Neurology, University Hospital MútuaTerrassa, Barcelona, Spain.
Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain.

Margaret A Pericak-Vance (MA)

The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.

Rachel Raybould (R)

UKDRI Cardiff, School of Medicine, Cardiff University, Cardiff, UK.

Richard Redon (R)

Université de Nantes, Centre Hospitalier Universitaire Nantes, Centre National de la Recherche Scientifique, INSERM, l'institut du Thorax, Nantes, France.

Marcel J T Reinders (MJT)

Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands.

Anne-Claire Richard (AC)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France.

Steffi G Riedel-Heller (SG)

Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.

Fernando Rivadeneira (F)

Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands.

Stéphane Rousseau (S)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France.

Natalie S Ryan (NS)

Dementia Research Centre, University College London Queen Square Institute of Neurology, London, UK.

Salha Saad (S)

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.

Pascual Sanchez-Juan (P)

Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
Neurology Service, Marqués de Valdecilla University Hospital (University of Cantabria and IDIVAL), Santander, Spain.

Gerard D Schellenberg (GD)

Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Philip Scheltens (P)

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.

Jonathan M Schott (JM)

Dementia Research Centre, University College London Queen Square Institute of Neurology, London, UK.

Davide Seripa (D)

Laboratory for Advanced Hematological Diagnostics, Department of Hematology and Stem Cell Transplant, Lecce, Italy.

Sudha Seshadri (S)

Framingham Heart Study, Framingham, MA, USA.
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.

Daoud Sie (D)

Genome Diagnostics, Department of Human Genetics, VU University, AmsterdamUMC (location VUmc), Amsterdam, the Netherlands.

Erik A Sistermans (EA)

Genome Diagnostics, Department of Human Genetics, VU University, AmsterdamUMC (location VUmc), Amsterdam, the Netherlands.

Sandro Sorbi (S)

Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence, Italy.
IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Resie van Spaendonk (R)

Genome Diagnostics, Department of Human Genetics, VU University, AmsterdamUMC (location VUmc), Amsterdam, the Netherlands.

Gianfranco Spalletta (G)

Laboratory of Neuropsychiatry, Department of Clinical and Behavioral Neurology, Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Rome, Italy.

Niccolo' Tesi (N)

Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands.

Betty Tijms (B)

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.

André G Uitterlinden (AG)

Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands.

Sven J van der Lee (SJ)

Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
Delft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands.

Pieter Jelle Visser (PJ)

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.

Michael Wagner (M)

Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany.
German Center for Neurodegenerative Diseases, Bonn, Germany.

David Wallon (D)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Neurology and CNRMAJ, Rouen, France.

Li-San Wang (LS)

Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Aline Zarea (A)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Neurology and CNRMAJ, Rouen, France.

Jordi Clarimon (J)

Department of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Biomedical Research Networking Center on Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.

John C van Swieten (JC)

Department of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.

Michael D Greicius (MD)

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.

Jennifer S Yokoyama (JS)

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Carlos Cruchaga (C)

Neurogenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.
Psychiatry Department, Washington University School of Medicine, St Louis, MO, USA.
Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA.

John Hardy (J)

Reta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.

Alfredo Ramirez (A)

Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.
Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany.
German Center for Neurodegenerative Diseases, Bonn, Germany.
Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

Simon Mead (S)

Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases, London, UK.

Wiesje M van der Flier (WM)

Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.

Cornelia M van Duijn (CM)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Nuffield Department of Population Health Oxford University, Oxford, UK.

Julie Williams (J)

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics,, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.

Gaël Nicolas (G)

Université Rouen Normandie, INSERM U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France. gaelnicolas@hotmail.com.

Céline Bellenguez (C)

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, Lille, France.

Jean-Charles Lambert (JC)

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, Lille, France. jean-charles.lambert@pasteur-lille.fr.

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