Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease
Por:
Holstege, H, Hulsman, M, Charbonnier, C, Grenier-Boley, B, Quenez, O, Grozeva, D, van Rooij, JGJ, Sims, R, Ahmad, S, Amin, N, Norsworthy, PJ, Dols-Icardo, O, Hummerich, H, Kawalia, A, Amouyel, P, Beecham, GW, Berr, C, Bis, JC, Boland, A, Bossu, P, Bouwman, F, Bras, J, Campion, D, Cochran, JN, Daniele, A, Dartigues, JF, Debette, S, Deleuze, JF, Denning, N, DeStefano, AL, Farrer, LA, Fernandez, MV, Fox, NC, Galimberti, D, Genin, E, Gille, JJP, Le Guen, Y, Guerreiro, R, Haines, JL, Holmes, C, Ikram, MA, Ikram, MK, Jansen, IE, Kraaij, R, Lathrop, M, Lemstra, AW, Lleo, A, Luckcuck, L, Mannens, MMAM, Marshall, R, Martin, ER, Masullo, C, Mayeux, R, Mecocci, P, Meggy, A, Mol, MO, Morgan, K, Myers, RM, Nacmias, B, Naj, AC, Napolioni, V, Pasquier, F, Pastor, P, Pericak-Vance, MA, Raybould, R, Redon, R, Reinders, MJT, Richard, AC, Riedel-Heller, SG, Rivadeneira, F, Rousseau, S, Ryan, NS, Saad, S, Sanchez-Juan, P, Schellenberg, GD, Scheltens, P, Schott, JM, Seripa, D, Seshadri, S, Sie, D, Sistermans, EA, Sorbi, S, van Spaendonk, R, Spalletta, G, Tesi, N, Tijms, B, Uitterlinden, AG, van der Lee, SJ, Visser, PJ, Wagner, M, Wallon, D, Wang, LS, Zarea, A, Clarimon, J, van Swieten, JC, Greicius, MD, Yokoyama, JS, Cruchaga, C, Hardy, J, Ramirez, A, Mead, S, van der Flier, WM, van Duijn, CM, Williams, J, Nicolas, G, Bellenguez, C, Lambert, JC
Publicada:
1 dic 2022
Ahead of Print:
1 nov 2022
Resumen:
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-beta precursor protein processing, amyloid-beta aggregation, lipid metabolism and microglial function in AD.
Filiaciones:
Holstege, H:
Vrije Univ Amsterdam, Amsterdam UMC Locat VUmc, Human Genet, Genom Neurodegenerat Dis & Aging, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Hulsman, M:
Vrije Univ Amsterdam, Amsterdam UMC Locat VUmc, Human Genet, Genom Neurodegenerat Dis & Aging, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Charbonnier, C:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CHU Rouen, Dept Genet, Rouen, France
CNRMAJ, Rouen, France
Grenier-Boley, B:
Univ Lille, INSERM, Ctr Hosp Univ Lille, Inst Pasteur Lille,U1167 RID AGE Facteurs Risque, Lille, France
Quenez, O:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CHU Rouen, Dept Genet, Rouen, France
CNRMAJ, Rouen, France
Grozeva, D:
Cardiff Univ, Med Res Council Ctr Neuropsychiat Genet & Genom, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
van Rooij, JGJ:
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Sims, R:
Cardiff Univ, Med Res Council Ctr Neuropsychiat Genet & Genom, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Ahmad, S:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Leiden Acad Ctr Drug Res, Leiden, Netherlands
Amin, N:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Norsworthy, PJ:
UCL, Med Res Council Prion Unit Univ Coll London, Inst Prion Dis, London, England
Dols-Icardo, O:
Univ Autonoma Barcelona, Dept Neurol, II B St Pau, Hosp Santa Creu & St Pau, Barcelona, Spain
Natl Inst Hlth Carlos III, Biomed Res Networking Ctr Neurodegenerat Dis, Madrid, Spain
Hummerich, H:
UCL, Med Res Council Prion Unit Univ Coll London, Inst Prion Dis, London, England
Kawalia, A:
Univ Cologne, Fac Med, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, Cologne, Germany
Univ Cologne, Univ Hosp Cologne, Cologne, Germany
Amouyel, P:
Univ Lille, INSERM, Ctr Hosp Univ Lille, Inst Pasteur Lille,U1167 RID AGE Facteurs Risque, Lille, France
Beecham, GW:
Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA
Berr, C:
Univ Montpellier, INSERM, Inst Neurosci Montpellier, Montpellier, France
Bis, JC:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Boland, A:
Univ Paris Saclay, Commissariat Energie Atom & Energies Alternat, Ctr Natl Rech Genom Humaine Evry, Gif Sur Yvette, France
Bossu, P:
Ist Ricovero & Cura Carattere Sci Santa Lucia Fdn, Dept Clin & Behav Neurol, Expt Neuro Psychobiol Lab, Rome, Italy
Bouwman, F:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Bras, J:
Van Andel Inst, Dept Neurodegenerat Sci, Grand Rapids, MI USA
Michigan State Univ, Div Psychiat & Behav Med, Coll Human Med, Grand Rapids, MI USA
Campion, D:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CHU Rouen, Dept Genet, Rouen, France
CNRMAJ, Rouen, France
Cochran, JN:
Hudson Alpha Inst Biotechnol, Huntsville, AL USA
Daniele, A:
Univ Cattolica Sacro Cuore, Fdn Policlin Univ A Gemelli Ist Ricovero & Cura C, Dept Neurosci, Rome, Italy
Dartigues, JF:
Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Debette, S:
Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, Bordeaux, France
Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France
Deleuze, JF:
Univ Paris Saclay, Commissariat Energie Atom & Energies Alternat, Ctr Natl Rech Genom Humaine Evry, Gif Sur Yvette, France
Denning, N:
Cardiff Univ, Sch Med, UKDRI Cardiff, Cardiff, Wales
DeStefano, AL:
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Farrer, LA:
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Boston Univ, Dept Epidemiol, Boston, MA USA
Boston Univ, Dept Med Biomed Genet, Boston, MA USA
Fernandez, MV:
Washington Univ, Sch Med, Neurogen & Informat Ctr, St Louis, MO USA
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
Fox, NC:
UCL, Dementia Res Ctr, Queen Sq Inst Neurol, London, England
Galimberti, D:
Osped Policlin, Fdn Ist Ricovero & Cura Carattere Sci Ca Granda, Milan, Italy
Univ Milan, Milan, Italy
Genin, E:
Univ Brest, INSERM, Etab Francais Sang, Ctr Hosp Univ Brest,Unite Mixte Rech 1078,GGB, Brest, France
Gille, JJP:
Vrije Univ Amsterdam, Dept Human Genet, AmsterdamUMC Locat VUmc, Genome Diagnost, Amsterdam, Netherlands
Le Guen, Y:
Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA
Guerreiro, R:
Van Andel Inst, Dept Neurodegenerat Sci, Grand Rapids, MI USA
Michigan State Univ, Div Psychiat & Behav Med, Coll Human Med, Grand Rapids, MI USA
Haines, JL:
Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA
Holmes, C:
Univ Southampton, Fac Med Clin & Expt Sci, Southampton, Hants, England
Ikram, MA:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Ikram, MK:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Jansen, IE:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ, Ctr Neurogen & Cognit Res, Amsterdam Neurosci, Dept Complex Trait Genet, Amsterdam, Netherlands
Kraaij, R:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Lathrop, M:
McGill Univ, Montreal, PQ, Canada
Genome Quebec Innovat Ctr, Montreal, PQ, Canada
Lemstra, AW:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Lleo, A:
Univ Autonoma Barcelona, Dept Neurol, II B St Pau, Hosp Santa Creu & St Pau, Barcelona, Spain
Natl Inst Hlth Carlos III, Biomed Res Networking Ctr Neurodegenerat Dis, Madrid, Spain
Luckcuck, L:
Cardiff Univ, Med Res Council Ctr Neuropsychiat Genet & Genom, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Mannens, MMAM:
Univ Amsterdam, Amsterdam Reprod & Dev Res Inst, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Marshall, R:
Cardiff Univ, Med Res Council Ctr Neuropsychiat Genet & Genom, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Martin, ER:
Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA
Univ Miami, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL USA
Masullo, C:
Univ Cattolica Sacro Cuore, Inst Neurol, Rome, Italy
Mayeux, R:
Columbia Univ, Taub Inst Alzheimers Dis & Aging Brain, Dept Neurol, New York, NY USA
Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA
Mecocci, P:
Univ Perugia, Inst Gerontol & Geriatr, Dept Med & Surg, Perugia, Italy
Meggy, A:
Cardiff Univ, Sch Med, UKDRI Cardiff, Cardiff, Wales
Mol, MO:
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
Morgan, K:
Univ Nottingham, Sch Life Sci, Human Genet, Nottingham, England
Myers, RM:
Hudson Alpha Inst Biotechnol, Huntsville, AL USA
Nacmias, B:
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
IRCCS Fdn Don Carlo Gnocchi, Florence, Italy
Naj, AC:
Univ Penn, Penn Neurodegenerat Genom Ctr, Dept Biostat Epidemiol & Informat, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Penn Neurodegenerat Genom Ctr, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA
Napolioni, V:
Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA
Univ Camerino, Sch Biosci & Vet Med, Genom & Mol Epidemiol Lab, Camerino, Italy
Pasquier, F:
Univ Lille, INSERM, Ctr Hosp Univ Lille,Licend, UMR1172,Resources & Res Memory Ctr MRRC Distalz, Lille, France
Pastor, P:
Univ Hosp MutuaTerrassa, Dept Neurol, Fundacio Docencia & Recerca MutuaTerrassa, Barcelona, Spain
Univ Hosp MutuaTerrassa, Dept Neurol, Movement Disorders Unit, Barcelona, Spain
Hosp Univ Mutua Terrassa, Dept Neurol, Memory Disorders Unit, Barcelona, Spain
Pericak-Vance, MA:
Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA
Univ Miami, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL USA
Raybould, R:
Cardiff Univ, Sch Med, UKDRI Cardiff, Cardiff, Wales
Redon, R:
Univ Nantes, Ctr Hosp Univ Nantes, Ctr Natl Rech Sci,INSERM, Inst Thorax, Nantes, France
Reinders, MJT:
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Richard, AC:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CHU Rouen, Dept Genet, Rouen, France
CNRMAJ, Rouen, France
Riedel-Heller, SG:
Univ Leipzig, Inst Social Med Occupat Hlth & Publ Hlth, Leipzig, Germany
Rivadeneira, F:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Rousseau, S:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CHU Rouen, Dept Genet, Rouen, France
CNRMAJ, Rouen, France
Ryan, NS:
UCL, Dementia Res Ctr, Queen Sq Inst Neurol, London, England
Saad, S:
Cardiff Univ, Med Res Council Ctr Neuropsychiat Genet & Genom, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Sanchez-Juan, P:
Natl Inst Hlth Carlos III, Biomed Res Networking Ctr Neurodegenerat Dis, Madrid, Spain
Univ Cantabria, Neurol Serv, Marques de Valdecilla Univ Hosp, Santander, Spain
IDIVAL, Santander, Spain
Schellenberg, GD:
Univ Penn, Penn Neurodegenerat Genom Ctr, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA
Scheltens, P:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Schott, JM:
UCL, Dementia Res Ctr, Queen Sq Inst Neurol, London, England
Seripa, D:
Dept Hematol & Stem Cell Transplant, Lab Adv Hematol Diagnost, Lecce, Italy
Seshadri, S:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
Dept Psychiat, San Antonio, TX USA
Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
Sie, D:
Vrije Univ Amsterdam, Dept Human Genet, AmsterdamUMC Locat VUmc, Genome Diagnost, Amsterdam, Netherlands
Sistermans, EA:
Vrije Univ Amsterdam, Dept Human Genet, AmsterdamUMC Locat VUmc, Genome Diagnost, Amsterdam, Netherlands
Sorbi, S:
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
IRCCS Fdn Don Carlo Gnocchi, Florence, Italy
van Spaendonk, R:
Vrije Univ Amsterdam, Dept Human Genet, AmsterdamUMC Locat VUmc, Genome Diagnost, Amsterdam, Netherlands
Spalletta, G:
Ist Ricovero & Cura Carattere Sci Santa Lucia Fdn, Dept Clin & Behav Neurol, Lab Neuropsychiat, Rome, Italy
Tesi, N:
Vrije Univ Amsterdam, Amsterdam UMC Locat VUmc, Human Genet, Genom Neurodegenerat Dis & Aging, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Tijms, B:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Uitterlinden, AG:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
van der Lee, SJ:
Vrije Univ Amsterdam, Amsterdam UMC Locat VUmc, Human Genet, Genom Neurodegenerat Dis & Aging, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Visser, PJ:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Wagner, M:
Univ Hosp Bonn, Med Fac, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
German Ctr Neurodegenerat Dis, Bonn, Germany
Wallon, D:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CNRMAJ, Rouen, France
CHU Rouen, Dept Neurol, Rouen, France
Wang, LS:
Univ Penn, Penn Neurodegenerat Genom Ctr, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA
Zarea, A:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CNRMAJ, Rouen, France
CHU Rouen, Dept Neurol, Rouen, France
Clarimon, J:
Univ Autonoma Barcelona, Dept Neurol, II B St Pau, Hosp Santa Creu & St Pau, Barcelona, Spain
Natl Inst Hlth Carlos III, Biomed Res Networking Ctr Neurodegenerat Dis, Madrid, Spain
van Swieten, JC:
Erasmus MC, Dept Neurol, Rotterdam, Netherlands
Greicius, MD:
Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA
Yokoyama, JS:
Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA
Cruchaga, C:
Washington Univ, Sch Med, Neurogen & Informat Ctr, St Louis, MO USA
Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
Hardy, J:
UCL, Dept Mol Neurosci, Inst Neurol, Reta Lila Weston Res Labs, London, England
Ramirez, A:
Univ Cologne, Fac Med, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, Cologne, Germany
Univ Cologne, Univ Hosp Cologne, Cologne, Germany
Dept Psychiat, San Antonio, TX USA
Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
Univ Hosp Bonn, Med Fac, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
German Ctr Neurodegenerat Dis, Bonn, Germany
Univ Cologne, Cluster Excellence Cellular Stress Responses Agin, Cologne, Germany
Mead, S:
UCL, Med Res Council Prion Unit Univ Coll London, Inst Prion Dis, London, England
van der Flier, WM:
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC Locat VUmc, Neurol, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
van Duijn, CM:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Williams, J:
Cardiff Univ, Med Res Council Ctr Neuropsychiat Genet & Genom, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Nicolas, G:
Univ Rouen Normandie, INSERM U1245, Rouen, France
CHU Rouen, Dept Genet, Rouen, France
CNRMAJ, Rouen, France
Bellenguez, C:
Univ Lille, INSERM, Ctr Hosp Univ Lille, Inst Pasteur Lille,U1167 RID AGE Facteurs Risque, Lille, France
Lambert, JC:
Univ Lille, INSERM, Ctr Hosp Univ Lille, Inst Pasteur Lille,U1167 RID AGE Facteurs Risque, Lille, France
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