title: 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.
authors: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors: G
authors: G
authors: Nicolas
authors: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors: C
authors: C
authors: Charbonnier
authors: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors: D
authors: D
authors: Wallon
authors: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.
authors: O
authors: O
authors: Quenez
authors: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors: C
authors: C
authors: Bellenguez
authors: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors: B
authors: B
authors: Grenier-Boley
authors: CNR-MAJ, Rouen University Hospital, Rouen, France.
authors: S
authors: S
authors: Rousseau
authors: CNR-MAJ, Rouen University Hospital, Rouen, France.
authors: A-C
authors: AC
authors: Richard
authors: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
authors: A
authors: A
authors: Rovelet-Lecrux
authors: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
authors: K
authors: K
authors: Le Guennec
authors: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors: D
authors: D
authors: Bacq
authors: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors: J-G
authors: JG
authors: Garnier
authors: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors: R
authors: R
authors: Olaso
authors: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors: A
authors: A
authors: Boland
authors: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors: V
authors: V
authors: Meyer
authors: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.|Fondation Jean Dausset, Centre d'études du Polymorphisme Humain, Paris, France.
authors: J-F
authors: JF
authors: Deleuze
authors: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors: P
authors: 0000-0001-9088-234X
authors: P
authors: Amouyel
authors: McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
authors: H M
authors: HM
authors: Munter
authors: McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
authors: G
authors: G
authors: Bourque
authors: McGill University and Génome Québec Innovation Centre, Montréal, QC, Canada.
authors: M
authors: M
authors: Lathrop
authors: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.
authors: T
authors: T
authors: Frebourg
authors: Inserm UMR 1087, l'institut du Thorax, CHU Nantes, Nantes, France.|CNRS, UMR 6291, Université de Nantes, Nantes, France.
authors: R
authors: R
authors: Redon
authors: Inserm U897, Univ Bordeaux, Bordeaux, France.
authors: L
authors: L
authors: Letenneur
authors: Inserm U897, Univ Bordeaux, Bordeaux, France.
authors: J-F
authors: JF
authors: Dartigues
authors: Inserm UMR1078, CHU Brest, Univ Bretagne Occidentale, Brest, France.
authors: E
authors: E
authors: Génin
authors: Inserm, U1167, Lille, France.|Institut Pasteur de Lille, Lille, France.|Université Lille-Nord de France, Lille, France.
authors: J-C
authors: JC
authors: Lambert
authors: Department of Genetics, Rouen University Hospital, Rouen, France.|Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Neurology, Rouen University Hospital, Rouen, France.
authors: D
authors: D
authors: Hannequin
authors: Inserm U1079, Rouen University, IRIB, Normandy University, Rouen, France.|CNR-MAJ, Rouen University Hospital, Rouen, France.|Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.
authors: D
authors: D
authors: Campion
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D059472:Exome; D005260:Female; D005602:France; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016017:Odds Ratio; D012307:Risk Factors
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; C102582:SORL1 protein, human