Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes
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Published:2022-06-28
Issue:1
Volume:14
Page:
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ISSN:1756-994X
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Container-title:Genome Medicine
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language:en
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Short-container-title:Genome Med
Author:
Schramm CatherineORCID, Charbonnier CamilleORCID, Zaréa Aline, Lacour Morgane, Wallon David, 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, 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, Alarcon Flora, Campion Dominique, Nuel Grégory, Nicolas GaëlORCID, , , ,
Abstract
Abstract
Background
Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants 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.
Methods
We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-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 of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia.
Results
SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE-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 of SORL1-LoF variant carriers in case-control study data.
Conclusions
We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.
Funder
Fondation pour la recherche médicale Fondation pour le recherche médicale Fondation Alzheimer Association France Alzheimer Agence Nationale pour la Recherche
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
Reference42 articles.
1. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63:168–74. 2. Nicolas G, Charbonnier C, Campion D. From common to rare variants: the genetic component of Alzheimer disease. Hum Hered. 2016;81:129–41. 3. Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O, et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011;16:903–7. 4. Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022;54:412–36. 5. Lanoiselée H-M, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: a genetic screening study of familial and sporadic cases. PLoS Med. 2017;14:e1002270.
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