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


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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This study was funded by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC 2008/067), the CNR-MAJ, the JPND PERADES and France Génomique. This work was supported by Labex GENMED ANR-10-LABX-0013, the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease). The funding sources had no specific roles.

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Correspondence to D Campion.

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Didier Hannequin, Dominique Campion, David Wallon, Olivier Martinaud, Gaël Nicolas (Centre Hospitalo-Universitaire (CHU), Rouen); Olivier Godefroy (CHU Amiens); Frédérique Etcharry-Bouyx, Valérie Chauviré (CHU Angers); Ludivine Chamard, Eric Berger, Eloi Magnin (CHU Besancon); Jean-Francois Dartigues, Sophie Auriacombe (CHU Bordeaux); Vincent de la Sayette, Fausto Viader (CHU Caen); Dominique Castan (CH Castres), Elsa Dionet (CHU Clermont-Ferrand); Francois Sellal (CH Colmar); Olivier Rouaud, Christel Thauvin (CHU Dijon); Olivier Moreaud, Mathilde Sauvée (CHU Grenoble); Adeline Rollin-Sillaire, Stéphanie Bombois, Marie-Anne Mackowiak, Vincent Deramecourt, Florence Pasquier (CHU Lille); Maïté Formaglio, Hélène Mollion, Isabelle Roullet-Solignac, Alain Vighetto, Bernard Croisile (CHU Lyon); Mira Didic, Olivier Félician, Lejla Koric, Mathieu Ceccaldi (CHU Marseille); Audrey Gabelle, Cecilia Marelli, Jacques Touchon, Pierre Labauge (CHU Montpellier); Thérèse Jonveaux (CHU Nancy); Martine Vercelletto, Claire Boutoleau-Bretonnière (CHU Nantes); Giovanni Castelnovo (CHU Nimes); David Renaud, Philippe Robert (CHU de Nice); Claire Paquet, Julien Dumurgier, Jacques Hugon (CHU Lariboisière, Paris); Agnès Michon, Isabelle Le Ber, Bruno Dubois, Charles Duyckaerts (CHU La Salpêtrière, Paris); Foucauld De Boisgueheneuc (CHU Poitiers); Serge Belliard (CHU Rennes); Serge Bakchine (CHU de Reims); Marie-Odile Barrellon, Bernard Laurent (CHU Saint-Etienne); Frédéric Blanc, Christine Tranchant (CHU Strasbourg); Jérémie Pariente, Michèle Puel (CHU Toulouse); Caroline Hommet, Karl Mondon (CHU Tours).

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Nicolas, G., Charbonnier, C., Wallon, D. et al. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Mol Psychiatry 21, 831–836 (2016).

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