Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

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. 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. 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 ~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. Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Authors

Institutions

Publication Details

Journal
Molecular Neurodegeneration
Published
2025-12-01
DOI
https://doi.org/10.1186/s13024-025-00907-z
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.82
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

Yann Le Guen, Rita Guerreiro, Camille Charbonnier, Anita L. DeStefano et al.
1 citations
Molecular Neurodegeneration
Genomics and Rare Diseases
1.82
article

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

Yann Le Guen, Rita Guerreiro, Camille Charbonnier, Anita L. DeStefano, Marcel M. A. M. Mannens, Najaf Amin, Marc Hulsman, Jean‐Charles Lambert, John Cornelis Van Swieten, Holger Hummerich, Marcel J. T. Reinders, Olivier Quenez, Sandro Sorbi, Emmanuelle Génin, Sudha S. Seshadri, Alberto Lleó, Rosalina van Spaendonk, R Myers, Cornelia M. van Duijn, Patrizia Mecocci, Nick C. Fox, Claudine Berr, Gary W. Beecham, Fernando Rivadeneira, Giulia Monti, Philip Scheltens, David Wallon, Pau Pástor, Pieter Jelle Visser, Betty Marije Tijms, Alfredo Ramı́rez, Fabrizio Piras, Afina W. Lemstra, André G. Uitterlinden, Wiesje M. van der Flier, Philippe Amouyel, Jeroen van Rooij, Jordi Clarimón, M. Arfan Ikram, Iain James Marshall, Robert Kraaij, Merel O. Mol, Li‐San Wang, Lindsay A. Farrer, Rachel Raybould, Carlos C Cruchaga, Rebecca Sims, Richard Redon, Femke H. Bouwman, Jonathan M. Schott, Henne Holstege, Jean‐François Dartigues, Carlo Masullo, Julie Williams, J. Nicholas Cochran, Daoud Sie, Adam C. Naj, Florence Pasquier, Detelina Grozeva, Valerio Napolioni, Benedetta Nacmias, Jennifer S. Yokoyama, Maartje J. Vogel, Joshua C. Bis, Christa de Geus, Clive Holmes, Anne Boland, Steffi Gerlinde Riedel-Heller, Céline Bellenguez, M Lathrop, Erik A. Sistermans, Pascual Sánchez‐Juan, Anne Mette G. Jensen, José Brás, M. Kamran Ikram, Anne‐Claire Richard, Olav M. Andersen, Stéphanie Debette, Richard P Mayeux, Gaël Nicolas, Daniela Galimberti, Alun Meggy, Oriol Dols‐Icardo, Eden R. Martin, Simon Mead, Natalie S. Ryan, María Victoria Fernández, Johan G. Olsen, Gerard D. Schellenberg, Paola Bossù, Matthijs W. J. de Waal, Shahzad Ahmad, Aline Zaréa, Nicola Denning, Yolande A.L. Pijnenburg, Niccoló Tesi, Antonio Daniele, Margaret A. Pericak-Vance, Amit Kawalia, Jean‐François Deleuze, Michael Wagner, Sven J. van der Lee, Benjamin Grenier‐Boley, Jonathan L. Haines, Stéphane Rousseau, Gilles Thomas
article en
1 citations

Abstract

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. 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. 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 ~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. Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Molecular NeurodegenerationVol. 20(1)
Università Cattolica del Sacro Cuore (IT), Boston University (US), Università di Camerino (IT), University of Copenhagen (DK), Centre National de la Recherche Scientifique (FR), Universidad de Cantabria (ES), Van Andel Institute (US), University of Miami (US), Université de Bordeaux (FR), Inserm (FR), Université de Bretagne Occidentale (FR), University of Cologne (DE), University of Milan (IT), Université de Montpellier (FR), University of Washington (US), Aarhus University (DK), Washington University in St. Louis (US), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), University of Perugia (IT), Université Paris-Saclay (FR), University Hospital Bonn (DE), Institut Pasteur de Lille (FR), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Hospital de Sant Pau (ES), Erasmus MC (NL), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), Centre Hospitalier Universitaire de Lille (FR), University of Oxford (GB), Centre National de Recherche en Génomique Humaine (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Marqués de Valdecilla University Hospital (ES), University Memory and Aging Center (US), Center for Human Genetics (US), Normandie Université (FR), Bordeaux Population Health (FR), Amsterdam Neuroscience (NL), Institute for Neurodegenerative Disorders (US), Instituto de Investigación Marqués de Valdecilla (ES), Don Carlo Gnocchi Foundation (IT), Institute of Human Genetics (PL), Hope Center for Neurological Disorders (US), UK Dementia Research Institute (GB), CEA Paris-Saclay (FR), Dr. John T. Macdonald Foundation (US), Centre Hospitalier Régional Universitaire de Brest (FR), Centre for Human Drug Research (NL), MRC Prion Unit (GB), Institute for Neurosciences of Montpellier (FR), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Institut du Thorax (FR), HudsonAlpha Institute for Biotechnology (US), McGill University and Génome Québec Innovation Centre (CA), Fondazione Santa Lucia (IT), National Hospital for Neurology and Neurosurgery (GB), Amsterdam University Medical Centers (NL), Hospital Universitari Germans Trias i Pujol (ES), University Hospital Cologne (DE), University of Southampton (GB), University of Florence (IT), University College London (GB), Amsterdam University of Applied Sciences (NL), Case Western Reserve University (US), Université de Rouen Normandie (FR), Columbia University (US), Cardiff University (GB), University of Pennsylvania (US), Vrije Universiteit Amsterdam (NL), Michigan State University (US), University of Amsterdam (NL), Erasmus University Rotterdam (NL), Leipzig University (DE), Stanford University (US), Nantes Université (FR), Delft University of Technology (NL)
Openalex Percentile: Top 11%
Genomics and Rare Diseases
1.82
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.