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

1 UFC - Université de Franche-Comté

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.

Domains: Life Sciences [q-bio]

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, 2016, 21 (6), pp.831-836. ⟨10.1038/mp.2015.121⟩. ⟨hal-03630222⟩