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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Schramm, Catherine | Charbonnier, Camille | 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 | Génin, Emmanuelle | 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 | 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 | Zarea, Aline | Boland, Anne | Deleuze, Jean-François | Olaso, Robert | Ahmad, Shahzad | Amouyel, Philippe | Berr, Claudine | Bossu, Paola | Bouwman, Femke | Bras, Jose | Campion, Dominique | Clarimon, Jordi | Daniele, Antonio | Dartigues, Jean-François | Debette, Stéphanie | Denning, Nicola | Dols-Icardo, Oriol | Fox, Nick | Galimberti, Daniela | Gille, Hans | Grenier-Boley, Benjamin | Grozeva, Detelina | Guerreiro, Rita | Hardy, John | 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 | Lleo, Alberto | Luckcuck, Lauren | Mannens, Marcel | Marshall, Rachel | Masullo, Carlo | Mead, Simon | Mecocci, Patrizia | Meggy, Alun | Mol, Merel | Morgan, Kevin | Nacmias, Benedetta | Norsworthy, Penny | Pastor, Pau | Quenez, Olivier | Ramirez, Alfredo | Raybould, Rachel | Redon, Richard | Reinders, Marcel | Richard, Anne-Claire | Riedel-Heller, Steffi | Rivadeneira, Fernando | Rousseau, Stéphane | Ryan, Natalie | Saad, Salha | Sanchez-Juan, Pascual | Scheltens, Philip | Schott, Jonathan | Seripa, Davide | Sie, Daoud | Sims, Rebecca | Sistermans, Erik | Sorbi, Sandro | van Spaendonk, Resie | Spalleta, Gianfranco | Tesi, Nicćolo | Tijms, Betty | Uitterlinden, André | van der Flier, Wiesje | van der Lee, Sven | van Duijn, Cornelia | van Rooij, Jeroen | van Swieten, John | de Visser, Pieter | Wagner, Michael | Williams, Julie | Alarcon, Flora | Nuel, Grégory
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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.
