SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease
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1
Gaël Nicolas
- Function : Author
- PersonId : 9291
- IdHAL : gael-nicolas
- ORCID : 0000-0002-1671-8274
- IdRef : 08351483X
C Charbonnier
- Function : Author
David Wallon
- Function : Author
O Quenez
- Function : Author
C Bellenguez
- Function : Author
B Grenier-Boley
- Function : Author
S Rousseau
- Function : Author
A-C Richard
- Function : Author
A Rovelet-Lecrux
- Function : Author
K Le Guennec
- Function : Author
D Bacq
- Function : Author
J-G Garnier
- Function : Author
R Olaso
- Function : Author
A Boland
- Function : Author
V Meyer
- Function : Author
J-F Deleuze
- Function : Author
P Amouyel
- Function : Author
- PersonId : 756626
- ORCID : 0000-0001-9088-234X
- IdRef : 058556818
H Munter
- Function : Author
G Bourque
- Function : Author
M Lathrop
- Function : Author
T Frebourg
- Function : Author
R Redon
- Function : Author
L Letenneur
- Function : Author
J-F Dartigues
- Function : Author
E Génin
- Function : Author
J-C Lambert
- Function : Author
Didier Hannequin
- Function : Author
Dominique Campion
- Function : Author
Olivier Martinaud
- Function : Author
Olivier Godefroy
- Function : Author
- PersonId : 901333
- ORCID : 0000-0001-6789-6620
- IdRef : 068994737
Frédérique Etcharry-Bouyx
- Function : Author
- PersonId : 992844
Valérie Chauviré
- Function : Author
Ludivine Chamard
- Function : Author
Eric Berger
- Function : Author
Eloi Magnin
- Function : Author
- PersonId : 773699
- ORCID : 0000-0003-3036-9266
- IdRef : 144716755
Jean-Francois Dartigues
- Function : Author
Sophie Auriacombe
- Function : Author
Vincent de La Sayette
- Function : Author
Fausto Viader
- Function : Author
Dominique Castan
- Function : Author
Elsa Dionet
- Function : Author
François Sellal
- Function : Author
Olivier Rouaud
- Function : Author
- PersonId : 170297
- IdHAL : olivier-rouaud
- ORCID : 0000-0003-1640-9954
- IdRef : 067132049
Christel Thauvin
- Function : Author
Olivier Moreaud
- Function : Author
Mathilde Sauvée
- Function : Author
Adeline Rollin-Sillaire
- Function : Author
Stéphanie Bombois
- Function : Author
Marie-Anne Mackowiak
- Function : Author
Vincent Deramecourt
- Function : Author
Florence Pasquier
- Function : Author
Maïté Formaglio
- Function : Author
Hélène Mollion
- Function : Author
Isabelle Roullet-Solignac
- Function : Author
Alain Vighetto
- Function : Author
Bernard Croisile
- Function : Author
Mira Didic
- Function : Author
- PersonId : 757436
- ORCID : 0000-0001-7067-536X
Olivier Félician
- Function : Author
Lejla Koric
- Function : Author
Mathieu Ceccaldi
- Function : Author
- PersonId : 757312
- ORCID : 0000-0002-4924-6736
Audrey Gabelle
- Function : Author
- PersonId : 757644
- ORCID : 0000-0002-7648-9194
Cecilia Marelli
- Function : Author
Jacques Touchon
- Function : Author
Pierre Labauge
- Function : Author
- PersonId : 759958
- ORCID : 0000-0001-7759-8555
- IdRef : 059860367
Thérèse Jonveaux
- Function : Author
Martine Vercelletto
- Function : Author
Claire Boutoleau-Bretonnière
- Function : Author
Giovanni Castelnovo
- Function : Author
David Renaud
- Function : Author
Philippe Robert
- Function : Author
- PersonId : 757589
- ORCID : 0000-0002-0963-1728
- IdRef : 058009647
Claire Paquet
- Function : Author
Julien Dumurgier
- Function : Author
- PersonId : 764398
- ORCID : 0000-0003-2070-9706
Jacques Hugon
- Function : Author
Agnès Michon
- Function : Author
Isabelle Le Ber
- Function : Author
Bruno Dubois
- Function : Author
Charles Duyckaerts
- Function : Author
Foucauld de Boisgueheneuc
- Function : Author
Serge Belliard
- Function : Author
Serge Bakchine
- Function : Author
Marie-Odile Barrellon
- Function : Author
Bernard Laurent
- Function : Author
Frédéric Blanc
- Function : Author
- PersonId : 777350
- ORCID : 0000-0002-6714-3247
- IdRef : 153058056
Christine Tranchant
- Function : Author
Jérémie Pariente
- Function : Author
Michèle Puel
- Function : Author
Caroline Hommet
- Function : Author
Karl Mondon
- Function : Author
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.