Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes
Authors: Schramm Catherine , Charbonnier Camille , Zaréa Aline , Lacour Morgane , Wallon David ,   CNRMAJ collaborators, Andriuta Daniela , Anthony Pierre , Auriacombe Sophie , Balageas Anna-Chloé , Ballan Guillaume , Barbay Mélanie , Beaufils Emilie , Béjot Yannick , Belliard Serge , Benaiteau Marie , Bennys Karim , Blanc Frédéric , Bombois Stéphanie , Boutoleau Bretonnière Claire , Branger Pierre , Carlier Jasmine , Cartz-Piver Leslie , Cassagnaud Pascaline , Castelnovo Giovanni , Champion Christine , Chaussenot Annabelle , Ceccaldi Mathieu , Chauviré Valérie , Chen Yaohua , Cogez Julien , Cognat Emmanuel , Contegal-Callier Fabienne , Corneille Lea , Couratier Philippe , Courtemanche Hélène , Cretin Benjamin , Crinquette Charlotte , Croisille Bernard , Dauriat Benjamin , Dautricourt Sophie , de la Sayette Vincent , De liège Astrid , De Verdal Marie , Deffond Didier , Delpont Benoit , Demurger Florence , Deramecourt Vincent , Derollez Céline , Didic Mira , Diemert Giulia , Dionet Elsa , Diraison Philippe , Doan Aude , Doco Fenzy Martine , Dufournet Boris , Dumurgier Julien , Durand Hélène , Dutray Anaïs , Etcharry-Bouyx Frédérique , Formaglio Maïté , Gabelle Audrey , Gainche-Salmon Anne , Getenet Jean-Claude , Ginglinger Emmanuelle , Godefroy Olivier , Graber Mathilde , Gregoire Chloé , Grimaldi Stephan , Gueniat Julien , Gueriot Claude , Haffen Sophie , Hamelin Lorraine , Hannequin Didier , Hanta Cezara , Hardy Clémence , Hautecloque Geoffroy , Heitz Camille , Hourregue Claire , Jonveaux Thérèse , Jurici Snejana , Khoumri Catia , Koric Lejla , Krolak-Salmon Pierre , Labauge Pierre , Lacour Morgane , Lagarde Julien , Lanoiselée Hélène-Marie , Laurens Brice , Le Ber Isabelle , Le Guyader Gwenaël , Leblanc Amélie , Lebouvier Thibaud , Lippi Anaïs , Mackowiak Marie-Anne , Magnin Eloi , Marelli Cecilia , Martinaud Olivier , Maureille Aurélien , Milongo-Rigal Emilie , Mohr Sophie , Mollion Hélène , Moreaud Olivier , Morin Alexandre , Nicolas Gaël , Nivelle Julia , Noiray Camille , Ollagnon-Roman Elisabeth , Paquet Claire , Pariente Jérémie , Pasquier Florence , Perron Alexandre , Philippi Nathalie , Pichon Virginie , Planche Vincent , Poirsier Céline , Rafiq Marie , Rod-Olivieri Pauline , Rollin-Sillaire Adeline , Roué-Jagot Carole , Saracino Dario , Sarazin Marie , Sauvée Mathilde , Sellal François , Sirven Villaros Lila , Thauvin Christel , Tisserand Camille , Tomasino Christophe , Turpinat Cédric , Van Damme Laurène , Vercruysse Olivier , Voilly Alice , Wagemann Nathalie , Wallon David , Zarea Aline , Boland Anne , Deleuze Jean-François , Olaso Robert ,   ADES consortium, Ahmad Shahzad , Amouyel Philippe , Berr Claudine , Boland Anne , Bossu Paola , Bouwman Femke , Bras Jose , Campion Dominique , Charbonnier Camille , Clarimon Jordi , Daniele Antonio , Dartigues Jean-François , Debette Stéphanie , Deleuze Jean-François , Denning Nicola , Dols-Icardo Oriol , Fox Nick C. , Galimberti Daniela , Génin Emmanuelle , Gille Hans , Grenier-Boley Benjamin , Grozeva Detelina , Guerreiro Rita , Hardy John J. , Holmes Clive , Holstege Henne , Hulsman Marc , Hummerich Holger , Ikram M. Arfan , Ikram M. Kamran , Jansen Iris , Kawalia Amit , Kraaij Robert , Lambert Jean-Charles , Lathrop Marc , Lemstra Afina W. , Lleo Alberto , Luckcuck Lauren , Mannens Marcel M. A. M. , Marshall Rachel , Masullo Carlo , Mead Simon , Mecocci Patrizia , Meggy Alun , Mol Merel O. , Morgan Kevin , Nacmias Benedetta , Nicolas Gaël , Norsworthy Penny J. , Pasquier Florence , Pastor Pau , Quenez Olivier , Ramirez Alfredo , Raybould Rachel , Redon Richard , Reinders Marcel J. T. , Richard Anne-Claire , Riedel-Heller Steffi G. , Rivadeneira Fernando , Rousseau Stéphane , Ryan Natalie S. , Saad Salha , Sanchez-Juan Pascual , Scheltens Philip , Schott Jonathan M. , Seripa Davide , Sie Daoud , Sims Rebecca , Sistermans Erik , Sorbi Sandro , van Spaendonk Resie , Spalleta Gianfranco , Tesi Nicćolo , Tijms Betty , Uitterlinden André G. , van der Flier Wiesje M. , van der Lee Sven J. , van Duijn Cornelia M. , van Rooij Jeroen G. J. , van Swieten John C. , de Visser Pieter J. , Wagner Michael , Wallon David , Williams Julie , Zarea Aline ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI) database,   Alzheimer Disease Sequencing Project (ADSP), Alarcon Flora , Campion Dominique , Nuel Grégory , Nicolas Gaël 
Published: June 2022

AbstractBackgroundAlzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF)SORL1variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor,APOE-ε4, make such estimations difficult.MethodsWe proposed to estimate the age-related penetrance ofSORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers ofSORL1-LoF variants, stratified byAPOE-ε4, derived from the Rotterdam study (N= 12,255), and (ii) an age-dependent proportional hazard effect forSORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions ofAPOE-ε4-stratifiedSORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia.ResultsSORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 amongAPOE-ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions ofSORL1-LoF variant carriers in case-control study data.ConclusionsWe conclude thatSORL1-LoF variants should be interpreted in light ofAPOEgenotypes for future clinical applications.