Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

Catherine Schramm (1, 2) , Camille Charbonnier (1) , Aline Zaréa (3) , Morgane Lacour (4) , David Wallon (3) , Daniela Andriuta (5, 6, 7) , Pierre Anthony , Sophie Auriacombe (8) , Anna-Chloé Balageas (9) , Guillaume Ballan (10) , Mélanie Barbay (5, 6, 7) , Emilie Beaufils (9) , Yannick Béjot (11, 12, 13, 14, 15, 16, 17) , Serge Belliard (18) , Marie Benaiteau (19) , Karim Bennys (20) , Frédéric Blanc (21, 22, 23) , Stéphanie Bombois (24) , Claire Boutoleau Bretonnière (25) , Pierre Branger (26) , Jasmine Carlier (4) , Leslie Cartz-Piver (27) , Pascaline Cassagnaud , Giovanni Castelnovo , Christine Champion , Annabelle Chaussenot , Mathieu Ceccaldi , Valérie Chauviré , Yaohua Chen , Julien Cogez , Emmanuel Cognat , Fabienne Contegal-Callier , Lea Corneille , Philippe Couratier , Hélène Courtemanche , Benjamin Cretin , Charlotte Crinquette , Bernard Croisille , Benjamin Dauriat , Sophie Dautricourt , Vincent de la Sayette , Astrid de Liège , Marie de Verdal , Didier Deffond , Emmanuelle Génin (28) , Benoit Delpont , Florence Demurger , Vincent Deramecourt , Céline Derollez , Mira Didic , Giulia Diemert , Elsa Dionet , Philippe Diraison , Aude Doan , Martine Doco Fenzy , Boris Dufournet , Julien Dumurgier , Hélène Durand , Anaïs Dutray , Frédérique Etcharry-Bouyx , Maïté Formaglio , Audrey Gabelle , Anne Gainche-Salmon , Jean-Claude Getenet , Emmanuelle Ginglinger , Olivier Godefroy (5, 6, 7) , Mathilde Graber , Chloé Gregoire , Stephan Grimaldi , Julien Gueniat , Claude Gueriot , Sophie Haffen , Lorraine Hamelin , Didier Hannequin , Cezara Hanta , Clémence Hardy , Geoffroy Hautecloque , Camille Heitz , Claire Hourregue , Thérèse Jonveaux , Snejana Jurici , Catia Khoumri , Lejla Koric , Pierre Krolak-Salmon , Pierre Labauge , Morgane Lacour , Julien Lagarde , Hélène-Marie Lanoiselée , Brice Laurens , Isabelle Le Ber , Gwenaël Le Guyader , Amélie Leblanc , Thibaud Lebouvier , Anaïs Lippi , Marie-Anne Mackowiak , Eloi Magnin , Cecilia Marelli , Olivier Martinaud , Aurélien Maureille , Emilie Milongo-Rigal , Sophie Mohr , Hélène Mollion , Olivier Moreaud , Alexandre Morin , Gaël Nicolas , Julia Nivelle , Camille Noiray , Elisabeth Ollagnon-Roman , Claire Paquet , Jérémie Pariente , Florence Pasquier , Alexandre Perron , Nathalie Philippi , Virginie Pichon , Vincent Planche , Céline Poirsier , Marie Rafiq , Pauline Rod-Olivieri , Adeline Rollin-Sillaire , Carole Roué-Jagot , Dario Saracino , Marie Sarazin , Mathilde Sauvée , François Sellal , Lila Sirven Villaros , Christel Thauvin , Camille Tisserand , Christophe Tomasino , Cédric Turpinat , Laurène van Damme , Olivier Vercruysse , Alice Voilly , Nathalie Wagemann , David Wallon , Aline Zarea , Anne Boland , Jean-François Deleuze , Robert Olaso , Shahzad Ahmad , Philippe Amouyel , Claudine Berr , Anne Boland , Paola Bossu , Femke Bouwman , Jose Bras , Dominique Campion , Camille Charbonnier , Jordi Clarimon , Antonio Daniele , Jean-François Dartigues , Stéphanie Debette , Jean-François Deleuze , Nicola Denning , Oriol Dols-Icardo , Nick Fox , Daniela Galimberti , Hans Gille , Benjamin Grenier-Boley , Detelina Grozeva , Rita Guerreiro , John Hardy , Clive Holmes , Henne Holstege , Marc Hulsman , Holger Hummerich , M. Arfan Ikram , M. Kamran Ikram , Iris Jansen , Amit Kawalia , Robert Kraaij , Jean-Charles Lambert , Marc Lathrop , Afina Lemstra , Alberto Lleo , Lauren Luckcuck , Marcel Mannens , Rachel Marshall , Carlo Masullo , Simon Mead , Patrizia Mecocci , Alun Meggy , Merel Mol , Kevin Morgan , Benedetta Nacmias , Gaël Nicolas , Penny Norsworthy , Florence Pasquier , Pau Pastor , Olivier Quenez , Alfredo Ramirez , Rachel Raybould , Richard Redon , Marcel Reinders , Anne-Claire Richard , Steffi Riedel-Heller , Fernando Rivadeneira , Stéphane Rousseau , Natalie Ryan , Salha Saad , Pascual Sanchez-Juan , Philip Scheltens , Jonathan Schott , Davide Seripa , Daoud Sie , Rebecca Sims , Erik Sistermans , Sandro Sorbi , Resie van Spaendonk , Gianfranco Spalleta , Nicćolo Tesi , Betty Tijms , André Uitterlinden , Wiesje van der Flier , Sven van der Lee , Cornelia van Duijn , Jeroen van Rooij , John van Swieten , Pieter de Visser , Michael Wagner , David Wallon , Julie Williams , Aline Zarea , Flora Alarcon (29) , Dominique Campion , Grégory Nuel , Gaël Nicolas

1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 CHU Rouen
3 Service de neurologie [Rouen]
4 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
5 CHU Amiens-Picardie
6 LNFP - Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559
7 CNRMAJ - Centre national de référence pour les malades Alzheimer jeunes
8 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
9 CHU Trousseau [Tours]
10 CHCB - Centre Hospitalier de la Côte Basque
11 UB - Université de Bourgogne
12 Université Lille Nord (France)
13 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
14 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
15 Santé publique France - French National Public Health Agency [Saint-Maurice, France]
16 EPOPé [CRESS - U1153 / UMR_A 1125] - Obstetrical, Perinatal and Pediatric Epidemiology | Épidémiologie Obstétricale, Périnatale et Pédiatrique
17 Université Paris Descartes, Sorbonne Paris Cité
18 Service de Neurologie [CHU Rennes]
19 Département Neurologie [CHU Toulouse]
20 Département de neurologie [Montpellier]
21 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
22 ICube - Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie
23 CMRR Strasbourg - Centre Mémoire Ressources et Recherche [Strasbourg]
24 CHU Pitié-Salpêtrière [AP-HP]
25 CHU Nantes - Centre Hospitalier Universitaire de Nantes
26 Hôpital Côte de Nacre [CHU Caen]
27 EpiMaCT - Epidémiologie des Maladies Chroniques en zone tropicale
28 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
29 MAP5 - UMR 8145 - Mathématiques Appliquées Paris 5

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.

Domaines: Sciences du Vivant [q-bio]; Statistiques [stat]

Catherine Schramm, Camille Charbonnier, Aline Zaréa, Morgane Lacour, David Wallon, et al.. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Medicine, 2022, 14 (1), pp.69. ⟨10.1186/s13073-022-01070-6⟩. ⟨hal-03971905⟩