SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease
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Nicolas, Gaël | Charbonnier, C | Wallon, David | 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 | Bourque, G | Lathrop, M | Frebourg, T | Redon, R | Letenneur, L | Dartigues, J-F | Génin, E | Lambert, J-C | Hannequin, Didier | Campion, Dominique | Martinaud, Olivier | Godefroy, Olivier | Etcharry-Bouyx, Frédérique | Chauviré, Valérie | Chamard, Ludivine | Berger, Eric | Magnin, Eloi | Dartigues, Jean-Francois | Auriacombe, Sophie | de La Sayette, Vincent | Viader, Fausto | Castan, Dominique | Dionet, Elsa | Sellal, François | Rouaud, Olivier | Thauvin, Christel | Moreaud, Olivier | Sauvée, Mathilde | Rollin-Sillaire, Adeline | Bombois, Stéphanie | Mackowiak, Marie-Anne | Deramecourt, Vincent | Pasquier, Florence | Formaglio, Maïté | Mollion, Hélène | Roullet-Solignac, Isabelle | Vighetto, Alain | Croisile, Bernard | Didic, Mira | Félician, Olivier | Koric, Lejla | Ceccaldi, Mathieu | Gabelle, Audrey | Marelli, Cecilia | Touchon, Jacques | Labauge, Pierre | Jonveaux, Thérèse | Vercelletto, Martine | Boutoleau-Bretonnière, Claire | Castelnovo, Giovanni | Renaud, David | Robert, Philippe | Paquet, Claire | Dumurgier, Julien | Hugon, Jacques | Michon, Agnès | Le Ber, Isabelle | Dubois, Bruno | Duyckaerts, Charles | de Boisgueheneuc, Foucauld | Belliard, Serge | Bakchine, Serge | Barrellon, Marie-Odile | Laurent, Bernard | Blanc, Frédéric | Tranchant, Christine | Pariente, Jérémie | Puel, Michèle | Hommet, Caroline | Mondon, Karl
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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.
