Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease
Por:
Andersen, OM, de Waal, MWJ, Monti, G, Tesi, N, Jensen, AMG, De Geus, C, van Spaendonk, R, Vogel, M, Ahmad, S, Amin, N, Amouyel, P, Beecham, GW, Bellenguez, C, Berr, C, Bis, JC, Boland, A, Bossù, P, Bouwman, F, Bras, J, Charbonnier, C, Clarimon, J, Cruchaga, C, Daniele, A, Dartigues, JF, Debette, S, Deleuze, JF, Denning, N, Destefano, AL, Dols-Icardo, O, van Duijn, CM, Farrer, LA, Fernández, MV, van der Flier, WM, Fox, NC, Galimberti, D, Genin, E, Gille, JJP, Grenier-Boley, B, Grozeva, D, Guen, YL, Guerreiro, R, Haines, JL, Holmes, C, Hummerich, H, Ikram, MA, Ikram, MK, Kawalia, A, Kraaij, R, Lambert, JC, Lathrop, M, Lemstra, AW, Lleo, A, Myers, RM, Mannens, MMAM, Marshall, R, Martin, ER, Masullo, C, Mayeux, R, Mead, S, Mecocci, P, Meggy, A, Mol, MO, Nacmias, B, Naj, AC, Napolioni, V, Cochran, JN, Nicolas, G, Pasquier, F, Pastor, P, Pericak-Vance, MA, Pijnenburg, YAL, Piras, F, Quenez, O, Ramirez, A, Raybould, R, Redon, R, Reinders, MJT, Richard, AC, Riedel-Heller, SG, Rivadeneira, F, van Rooij, JGJ, Rousseau, S, Ryan, NS, Sanchez-Juan, P, Schellenberg, GD, Scheltens, P, Schott, JM, Seshadri, S, Sie, D, Sims, R, Sistermans, EA, Sorbi, S, van Swieten, JC, Tijms, B, Uitterlinden, AG, Visser, PJ, Wagner, M, Wallon, D, Wang, LS, Williams, J, Yokoyama, JS, Zarea, A, van der Lee, SJ, Olsen, JG, Hulsman, M, Holstege, H
Publicada:
1 dic 2025
Resumen:
Background: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer's Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear.
Methods: To identify high-priority missense variants (HPVs), we applied 'domain mapping of disease mutations' for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls.
Results: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is similar to 8-10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects.
Conclusion: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.
Filiaciones:
Andersen, OM:
Aarhus Univ, Dept Biomed, Aarhus, Denmark
de Waal, MWJ:
Vrije Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Monti, G:
Aarhus Univ, Dept Biomed, Aarhus, Denmark
Tesi, N:
Vrije Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Jensen, AMG:
Aarhus Univ, Dept Biomed, Aarhus, Denmark
De Geus, C:
Amsterdam UMC, Clin Genet, Human Genet, Amsterdam, Netherlands
van Spaendonk, R:
Vrije Univ Amsterdam, Genome Anal Lab, Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Vogel, M:
Vrije Univ Amsterdam, Genome Anal Lab, Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Ahmad, S:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
LACDR, Leiden, Netherlands
Amin, N:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Amouyel, P:
Univ Lille, CHU Lille, LabEx DISTALZ,RID AGE Facteurs Risque & Determinan, Inst Pasteur Lille,Inserm,U1167, Lille, France
Beecham, GW:
Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA
Bellenguez, C:
Univ Lille, CHU Lille, LabEx DISTALZ,RID AGE Facteurs Risque & Determinan, Inst Pasteur Lille,Inserm,U1167, Lille, France
Berr, C:
Univ Montpellier, INM Inst Neurosci Montpellier, Inserm, Montpellier, France
Bis, JC:
Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA
Boland, A:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, Evry, France
Bossù, P:
IrCCS Santa Lucia Fdn, Dept Clin & Behav Neurol, Expt Neuropsychobiol Lab, Rome, Italy
Bouwman, F:
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Bras, J:
Michigan State Univ, Coll Human Med, Div Psychiat & Behav Med, Grand Rapids, MI USA
Van Andel Inst, Dept Neurodegenerat Sci, Grand Rapids, MI USA
Charbonnier, C:
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, CNRMAJ, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Clarimon, J:
Univ Autonoma Barcelona, Neurol Dept, Memory Unit, St Quinti 77-79, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Recerca St Pau, St Quinti 77-79, Barcelona 08041, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Cruchaga, C:
Washington Univ, Psychiat Dept, Sch Med, St Louis, MO USA
Washington Univ, Sch Med, NeuroGenom & Informat Ctr, St Louis, MO USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
Daniele, A:
Fdn Policlin Univ A Gemelli IRCCS, Catholic Univ Sacred Heart, Dept Neurosci, Rome, Italy
Dartigues, JF:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, Bordeaux, France
Debette, S:
Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, Bordeaux, France
Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France
Deleuze, JF:
Univ Paris Saclay, Ctr Natl Rech Genom Humaine, CEA, Evry, 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
Dols-Icardo, O:
Univ Autonoma Barcelona, Neurol Dept, Memory Unit, St Quinti 77-79, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Recerca St Pau, St Quinti 77-79, Barcelona 08041, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
van Duijn, CM:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Farrer, LA:
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Dept Neurol, Sch Med, Boston, MA USA
Boston Univ, Dept Med Biomed Genet, Boston, MA USA
Fernández, MV:
Washington Univ, Psychiat Dept, Sch Med, St Louis, MO USA
Washington Univ, Sch Med, NeuroGenom & Informat Ctr, St Louis, MO USA
Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA
Fox, NC:
UCL, UK Dementia Res Inst, London, England
UCL Queen Sq Inst Neurol, Dementia Res Ctr, London, England
Galimberti, D:
Univ Milan, Milan, Italy
Osped Policlin, Fdn IRCCS CaGranda, Milan, Italy
Genin, E:
Univ Brest, UMR 1078, GGB, Inserm,EFS,CHU Brest, F-29200 Brest, France
Gille, JJP:
Vrije Univ Amsterdam, Genome Anal Lab, Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Grenier-Boley, B:
Univ Lille, CHU Lille, LabEx DISTALZ,RID AGE Facteurs Risque & Determinan, Inst Pasteur Lille,Inserm,U1167, Lille, France
Grozeva, D:
Cardiff Univ, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Guen, YL:
Stanford Univ, Dept Med, Quantitat Sci Unit, Stanford, CA USA
Guerreiro, R:
Michigan State Univ, Coll Human Med, Div Psychiat & Behav Med, Grand Rapids, MI USA
Van Andel Inst, Dept Neurodegenerat Sci, Grand Rapids, MI USA
Haines, JL:
Case Western Reserve Univ, Sch Med, Dept Populat & Quantitat Hlth Sci, Cleveland, OH USA
Holmes, C:
Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, England
Hummerich, H:
UCL, Inst Prion Dis, MRC Pr Unit, London, England
Ikram, MA:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Ikram, MK:
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands
Kawalia, A:
Fac Med, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, Cologne, Germany
Univ Hosp Cologne, Cologne, Germany
Kraaij, R:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Lambert, JC:
Univ Lille, CHU Lille, LabEx DISTALZ,RID AGE Facteurs Risque & Determinan, Inst Pasteur Lille,Inserm,U1167, Lille, France
Lathrop, M:
McGill Univ, Montreal, PQ, Canada
Genome Quebec Innovat Ctr, Montreal, PQ, Canada
Lemstra, AW:
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Lleo, A:
Univ Autonoma Barcelona, Neurol Dept, Memory Unit, St Quinti 77-79, Barcelona 08041, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Recerca St Pau, St Quinti 77-79, Barcelona 08041, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Myers, RM:
HudsonAlpha Inst Biotechnol, Huntsville, AL USA
Mannens, MMAM:
Univ Amsterdam, Amsterdam Reprod & Dev Res Inst Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Marshall, R:
Cardiff Univ, 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, Dept Neurol, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA
Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY USA
Mead, S:
UCL, Inst Prion Dis, MRC Pr Unit, London, England
Mecocci, P:
Univ Perugia, Dept Med & Surg, Div Gerontol & Geriatr, Perugia, Italy
Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden
Meggy, A:
Cardiff Univ, Sch Med, UKDRI Cardiff, Cardiff, Wales
Mol, MO:
Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands
Nacmias, B:
IRCCS Fdn Don Carlo Gnocchi, Florence, Italy
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
Naj, AC:
Univ Penn, Perelman Sch Med, Penn Neurodegenerat Genom Ctr, Dept Pathol & Lab Med, Philadelphia, PA USA
Univ Penn, Penn Neurodegenerat Genom Ctr, Perelman Sch Med, Dept Biostat Epidemiol & Informat, Philadelphia, PA USA
Napolioni, V:
Stanford Univ, Dept Med, Quantitat Sci Unit, Stanford, CA USA
Univ Camerino UNICAM, Sch Biosci & Vet Med, Genom & Mol Epidemiol GAME Lab, Camerino, Italy
Cochran, JN:
HudsonAlpha Inst Biotechnol, Huntsville, AL USA
Nicolas, G:
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, CNRMAJ, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Pastor, P:
Germans Trias & Pujol Res Inst IGTP, Badalona, 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
Pijnenburg, YAL:
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Piras, F:
IrCCS Santa Lucia Fdn, Dept Clin & Behav Neurol, Lab Neuropsychiat, Rome, Italy
Quenez, O:
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, CNRMAJ, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Ramirez, A:
Fac Med, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, Cologne, Germany
Univ Hosp Cologne, Cologne, Germany
Univ Cologne, Cluster Excellence Cellular Stress Responses Aging, Cologne, Germany
Dept Psychiat, San Antonio, TX USA
Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Hosp Bonn, Med Fac, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
Raybould, R:
Cardiff Univ, Sch Med, UKDRI Cardiff, Cardiff, Wales
Redon, R:
Univ Nantes, CNRS, Inst Thorax, INSERM,CHU Nantes, Nantes, France
Reinders, MJT:
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Richard, AC:
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, CNRMAJ, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 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:
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, CNRMAJ, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Ryan, NS:
UCL, UK Dementia Res Inst, London, England
UCL Queen Sq Inst Neurol, Dementia Res Ctr, London, England
Sanchez-Juan, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Cantabria, Marques de Valdecilla Univ Hosp, Neurol Serv, Santander, Spain
IDIVAL, Santander, Spain
Schellenberg, GD:
Univ Penn, Perelman Sch Med, Penn Neurodegenerat Genom Ctr, Dept Pathol & Lab Med, Philadelphia, PA USA
Scheltens, P:
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Schott, JM:
UCL, UK Dementia Res Inst, London, England
UCL Queen Sq Inst Neurol, Dementia Res Ctr, London, England
Seshadri, S:
Framingham Heart Dis Epidemiol Study, Framingham, MA USA
Boston Univ, Dept Neurol, Sch Med, Boston, MA USA
Dept Psychiat, San Antonio, TX USA
Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA
Sie, D:
Vrije Univ Amsterdam, Genome Anal Lab, Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Sims, R:
Cardiff Univ, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Sistermans, EA:
Vrije Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Univ Amsterdam, Amsterdam Reprod & Dev Res Inst Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Sorbi, S:
IRCCS Fdn Don Carlo Gnocchi, Florence, Italy
Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy
Tijms, B:
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Uitterlinden, AG:
Erasmus MC, Dept Internal Med, Rotterdam, Netherlands
Visser, PJ:
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Wagner, M:
German Ctr Neurodegenerat Dis DZNE, Bonn, Germany
Univ Hosp Bonn, Med Fac, Dept Neurodegenerat Dis & Geriatr Psychiat, Bonn, Germany
Wallon, D:
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, CNRMAJ, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Wang, LS:
Univ Penn, Perelman Sch Med, Penn Neurodegenerat Genom Ctr, Dept Pathol & Lab Med, Philadelphia, PA USA
Williams, J:
Cardiff Univ, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, Wales
Cardiff Univ, MRC UK Dementia Res Inst, Div Psychol Med, Cardiff, Wales
Yokoyama, JS:
Univ Calif San Francisco, Weill Inst Neurosci, Memory & Aging Ctr, Dept Neurol, San Francisco, CA USA
Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA USA
Zarea, A:
Normandie Univ, Univ Rouen Normandie, Dept Genet, Inserm,U1245, F-76000 Rouen, France
Normandie Univ, Univ Rouen Normandie, CNRMAJ, Inserm,U1245, F-76000 Rouen, France
CHU Rouen, F-76000 Rouen, France
Olsen, JG:
Univ Copenhagen, Dept Biol, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark
Hulsman, M:
Vrije Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Holstege, H:
Vrije Univ Amsterdam, Dept Human Genet, Amsterdam UMC, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Neurol, Amsterdam UMC, Amsterdam, Netherlands
Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands
Green Submitted, Green Published, gold
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