SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease
Abstract
The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.
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An enrichment for rare disruptive and putatively damaging variants in SORL1 were identified among EOAD cases.
“Notably, an enrichment for rare disruptive and putatively damaging variants in SORL1 were also identified among EOAD cases [155, 156].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [156]
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References 24 · Cited by 129
- Authors
- Nicolas, G., Charbonnier, C., Wallon, D., Quenez, O., Bellenguez, C., Grenier-Boley, B., Rousseau, S., Richard, A.-C., Rovelet-Lecrux, A., Le Guennec, K., Bacq, D., Garnier, J.-G., Olaso, R., Boland, A., Meyer, V, Deleuze, J.-F., Amouyel, P., Munter, H. M., Bourque, G., Lathrop, M., Frebourg, T., Redon, R., Letenneur, L., Dartigues, J.-F., Génin, E., Lambert, J.-C., Hannequin, D., Campion, D., collaborators, T. C.-M., Hannequin, D., Campion, D., Wallon, D., Martinaud, O., Nicolas, G., Godefroy, O., Etcharry-Bouyx, F., Chauviré, V., Chamard, L., Berger, E., Magnin, E., Dartigues, J.-F., Auriacombe, S., de la Sayette, V., Viader, F., Castan, D., Dionet, E., Sellal, F., Rouaud, O., Thauvin, C., Moreaud, O., Sauvée, M., Rollin-Sillaire, A., Bombois, S., Mackowiak, M.-A., Deramecourt, V., Pasquier, F., Formaglio, M., Mollion, H., Roullet-Solignac, I., Vighetto, A., Croisile, B., Didic, M., Félician, O., Koric, L., Ceccaldi, M., Gabelle, A., Marelli, C., Touchon, J., Labauge, P., Jonveaux, T., Vercelletto, M., Boutoleau-Bretonnière, C., Castelnovo, G., Renaud, D., Robert, P., Paquet, C., Dumurgier, J., Hugon, J., Michon, A., Le Ber, I., Dubois, B., Duyckaerts, C., De Boisgueheneuc, F., Belliard, S., Bakchine, S., Barrellon, M.-O., Laurent, B., Blanc, F., Tranchant, C., Pariente, J., Puel, M., Hommet, C., & Mondon, K.
- Affiliations
- Inserm (FR)
- Centre Hospitalier Universitaire de Rouen (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- McGill University and Génome Québec Innovation Centre (CA)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Charbonnier, C
- Quenez, O
- Bellenguez, C
- Olaso, R
- Boland, A
- Meyer, V
- Deleuze, J-F
- Amouyel, P
- Bourque, G
- Lathrop, M
- Redon, R
- Letenneur, L
- Génin, E
- Lambert, J-C
- Godefroy, Olivier
- Viader, Fausto
- Rouaud, Olivier
- Moreaud, Olivier
- Sauvée, Mathilde
- Bombois, Stéphanie
- Deramecourt, Vincent
- Pasquier, Florence
- Croisile, Bernard
- Didic, Mira
- Félician, Olivier
- Koric, Lejla
- Ceccaldi, Mathieu
- Gabelle, Audrey
- Labauge, Pierre
- Jonveaux, Thérèse
- Castelnovo, Giovanni
- Robert, Philippe
- Paquet, Claire
- Dumurgier, Julien
- Hugon, Jacques
- Dubois, Bruno
- Duyckaerts, Charles
- Belliard, Serge
- Laurent, Bernard
- Blanc, Frédéric
- Tranchant, Christine
- Pariente, Jérémie
- Venue
- Molecular Psychiatry
- Published
- 2015-08-25
- Volume
- 21
- Issue
- 6
- Pages
- 831-836
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W1151405824
- Cited by
- 129
- References
- 24
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 18 · 2023: 9 · 2022: 12 · 2021: 16 · 2020: 11 · 2019: 12 · 2018: 11 · 2017: 13 · 2016: 12
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- EU Joint Programme – Neurodegenerative Disease Research
- Agence Nationale de la Recherche (ANR-11-LABX-0009)
- 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, rare variants, early-onset Alzheimer's disease, familial Alzheimer's disease, amyloid-beta secretion, genetic risk factors, missense mutations, family history (medicine), exome sequencing
- MeSH terms
- Alleles, Alzheimer Disease, Female, France, Gene Frequency, Humans, Male, Middle Aged, Risk Factors, Genetic Variation, Odds Ratio, Case-Control Studies, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Genetic Predisposition to Disease, LDL-Receptor Related Proteins, Membrane Transport Proteins, Exome
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