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Mol Psychiatry. 2016 Jun;21(6):831-6. doi: 10.1038/mp.2015.121. Epub 2015 Aug 25.

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

Author information

1
Department of Genetics, Rouen University Hospital, Rouen, France.
2
Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
3
CNR-MAJ, Rouen University Hospital, Rouen, France.
4
Department of Neurology, Rouen University Hospital, Rouen, France.
5
Inserm, U1167, Lille, France.
6
Institut Pasteur de Lille, Lille, France.
7
Université Lille-Nord de France, Lille, France.
8
Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
9
Fondation Jean Dausset, Centre d'études du Polymorphisme Humain, Paris, France.
10
McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
11
Inserm UMR 1087, l'institut du Thorax, CHU Nantes, Nantes, France.
12
CNRS, UMR 6291, Université de Nantes, Nantes, France.
13
Inserm U897, Univ Bordeaux, Bordeaux, France.
14
Inserm UMR1078, CHU Brest, Univ Bretagne Occidentale, Brest, France.
15
Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.

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.

PMID:
26303663
DOI:
10.1038/mp.2015.121
[Indexed for MEDLINE]

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