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

Gaël Nicolas C Charbonnier David Wallon O Quenez C Bellenguez B Grenier-Boley S Rousseau A-C Richard A Rovelet-Lecrux K Le Guennec D Bacq J-G Garnier R Olaso A Boland V Meyer J-F Deleuze P Amouyel H Munter G Bourque M Lathrop T Frebourg R Redon L Letenneur J-F Dartigues E Génin J-C Lambert Didier Hannequin Dominique Campion Olivier Martinaud Olivier Godefroy Frédérique Etcharry-Bouyx Valérie Chauviré Ludivine Chamard Eric Berger Eloi Magnin 1 Jean-Francois Dartigues Sophie Auriacombe Vincent de La Sayette Fausto Viader Dominique Castan Elsa Dionet François Sellal Olivier Rouaud Christel Thauvin Olivier Moreaud Mathilde Sauvée Adeline Rollin-Sillaire Stéphanie Bombois Marie-Anne Mackowiak Vincent Deramecourt Florence Pasquier Maïté Formaglio Hélène Mollion Isabelle Roullet-Solignac Alain Vighetto Bernard Croisile Mira Didic Olivier Félician Lejla Koric Mathieu Ceccaldi Audrey Gabelle Cecilia Marelli Jacques Touchon Pierre Labauge Thérèse Jonveaux Martine Vercelletto Claire Boutoleau-Bretonnière Giovanni Castelnovo David Renaud Philippe Robert Claire Paquet Julien Dumurgier Jacques Hugon Agnès Michon Isabelle Le Ber Bruno Dubois Charles Duyckaerts Foucauld de Boisgueheneuc Serge Belliard Serge Bakchine Marie-Odile Barrellon Bernard Laurent Frédéric Blanc Christine Tranchant Jérémie Pariente Michèle Puel Caroline Hommet Karl Mondon 
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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https://hal-univ-fcomte.archives-ouvertes.fr/hal-03630222
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Submitted on : Monday, April 4, 2022 - 7:06:21 PM
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Gaël Nicolas, C Charbonnier, David Wallon, O Quenez, C Bellenguez, et al.. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease. Molecular Psychiatry, Nature Publishing Group, 2016, 21 (6), pp.831-836. ⟨10.1038/mp.2015.121⟩. ⟨hal-03630222⟩

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