A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
Open accessAbstract
The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.
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Using a large whole-exome-sequencing study, ten genes located in genome-wide loci were identified as having rare deleterious coding, splicing or LOF burden associations with LOAD (FDR P < 0.01), including ABCA7, TREM2, SORL1, TREML4, TAP2, PSMB8, PIP, STYX, RIN3, and KCNH6.
“we also identified ten genes located in our genome-wide loci as having rare deleterious coding, splicing or LOF burden associations with LOAD (false discovery rate (FDR) P < 0.01), including previously implicated rare-variant signals in ABCA7, TREM2, and SORL1 (refs. 14,49–55), and additional associations with TREML4 in the TREM2 locus, TAP2 and PSMB8 in the HLA-DRB1 locus, PIP in the EPHA1 locus,”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [51]
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- Authors
- Verheijen, J., Van den Bossche, T., van der Zee, J., Engelborghs, S., Sanchez-Valle, R., Lladó, A., Graff, C., Thonberg, H., Pastor, P., Ortega-Cubero, S., Pastor, M. A., Benussi, L., Ghidoni, R., Binetti, G., Clarimon, J., Lleó, A., Fortea, J., de Mendonça, A., Martins, M., Grau-Rivera, O., Gelpi, E., Bettens, K., Mateiu, L., Dillen, L., Cras, P., De Deyn, P. P., Van Broeckhoven, C., & Sleegers, K.
- Affiliations
- University of Antwerp (BE)
- Hospital Clínic de Barcelona (ES)
- Karolinska University Hospital (SE)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- Universitat Autònoma de Barcelona (ES)
- University of Lisbon (PT)
- Corresponding author
- Sleegers, Kristel
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2016-03-30
- Volume
- 132
- Issue
- 2
- Pages
- 213-224
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC4947104
- OpenAlex
- W2325841306
- Cited by
- 112
- References
- 59
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 10 · 2023: 11 · 2022: 15 · 2021: 16 · 2020: 12 · 2019: 5 · 2018: 13 · 2017: 13 · 2016: 3
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Fondazione Cassa di Risparmio di Pistoia e Pescia (2014.0365)
- Univerzita Karlova v Praze
- European Commission (305299)
- Fonds Wetenschappelijk Onderzoek (G043211N)
- Ministero della Salute (RF-2010-2319722, RF 2010)
- Ministerio de Economía y Competitividad (PI14/, PI12/, PI13/02434)
- Karolinska Institutet
- Vetenskapsrådet (2015-02926)
- Koning Boudewijnstichting
- Swedish Brain Power
- Stockholms Universitet
- Demensfonden
- Fondation pour la Recherche sur Alzheimer
- Fundação para a Ciência e a Tecnologia (SFRH/BPD/29354/2006)
- Instituto de Salud Carlos III (PI13/02434, PI14/00282, PI12/01311, PI14/)
- European Regional Development Fund (PI14/00282, PI13/02434)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- SORL1, early-onset Alzheimer's disease, rare variants, frameshift mutation, nonsense mutation, haploinsufficiency, nonsense-mediated mRNA decay, non-synonymous variants, European populations, premature stop codon, genetic risk
- MeSH terms
- Aged, Alzheimer Disease, Female, Gene Frequency, Humans, Male, Mutation, Risk, Genetic Variation, Age of Onset, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, LDL-Receptor Related Proteins, Membrane Transport Proteins, White People
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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