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

Catherine Schramm; Camille Charbonnier; Aline Zaréa; Morgane Lacour; David Wallon; Daniela Andriuta; Pierre Anthony; Sophie Auriacombe; Anna-Chloé Balageas; Guillaume Ballan; Mélanie Barbay; Emilie Beaufils; Yannick Béjot; Serge Belliard; Marie Benaiteau; Karim Bennys; Frédéric Blanc; Stéphanie Bombois; Claire Boutoleau Bretonnière; Pierre Branger; Jasmine Carlier; Leslie Cartz-Piver; 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; 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; 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; 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; Aline Zarea; Anne Boland; Jean-François Deleuze; Robert Olaso; Shahzad Ahmad; Philippe Amouyel; Claudine Berr; Paola Bossu; Femke Bouwman; Jose Bras; Dominique Campion; Jordi Clarimon; Antonio Daniele; Jean-François Dartigues; Stéphanie Debette; 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; Penny Norsworthy; 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; Julie Williams; Flora Alarcon; Grégory Nuel

doi:10.1186/s13073-022-01070-6

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

Catherine Schramm, Camille Charbonnier, Aline Zaréa, Morgane Lacour, David Wallon, Daniela Andriuta, Pierre Anthony, Sophie Auriacombe, Anna-Chloé Balageas, Guillaume Ballan, …

Genome Medicine, Vol.14(1)

12/2022

DOI: https://doi.org/10.1186/s13073-022-01070-6

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.

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Title: Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes
Creators - without role: Catherine Schramm - Normandie Université
Camille Charbonnier - Inserm
Aline Zaréa - Normandie Université
Morgane Lacour - Inserm
David Wallon - Normandie Université
Daniela Andriuta - Centre Hospitalier Universitaire Amiens-Picardie
Pierre Anthony
Sophie Auriacombe - Institut des Maladies Neurodégénératives
Anna-Chloé Balageas - Charmo University
Guillaume Ballan - Centre Hospitalier de la Côte Basque
Mélanie Barbay - Centre Hospitalier Universitaire Amiens-Picardie
Emilie Beaufils - Charmo University
Yannick Béjot - Université de Bourgogne
Serge Belliard - Service de Neurologie [CHU Rennes]
Marie Benaiteau - Département Neurologie [CHU Toulouse]
Karim Bennys - Département de neurologie [Montpellier]
Frédéric Blanc - Laboratoire des Sciences de l'Ingénieur, de l'Informatique et de l'Imagerie
Stéphanie Bombois - Charmo University
Claire Boutoleau Bretonnière - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
Pierre Branger - Hôpital Côte de Nacre [CHU Caen]
Jasmine Carlier - UNIROUEN - UFR Santé
Leslie Cartz-Piver - Institut d’Epidémiologie et de Neurologie Tropicale
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 - Génétique, Génomique Fonctionnelle et Biotechnologies
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 - Centre National de Recherche en Génomique Humaine
Jean-Claude Getenet
Emmanuelle Ginglinger
Olivier Godefroy - Centre Hospitalier Universitaire Amiens-Picardie
Mathilde Graber
Chloé Gregoire
Stephan Grimaldi
Julien Gueniat
Claude Gueriot
Sophie Haffen
Lorraine Hamelin
Didier Hannequin
Cezara Hanta
Clémence Hardy
Geoffroy Hautecloque
Camille Heitz - Normandie Université
Claire Hourregue
Thérèse Jonveaux
Snejana Jurici
Catia Khoumri
Lejla Koric
Pierre Krolak-Salmon
Pierre Labauge
Morgane Lacour - Inserm
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 - Inserm
Julia Nivelle
Camille Noiray - Inserm
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 - Centre National de Recherche en Génomique Humaine
Lila Sirven Villaros
Christel Thauvin
Camille Tisserand - Inserm
Christophe Tomasino
Cédric Turpinat
Laurène van Damme
Olivier Vercruysse
Alice Voilly
Nathalie Wagemann
David Wallon - Normandie Université
Aline Zarea - Normandie Université
Anne Boland - CEA Paris-Saclay
Jean-François Deleuze - Centre National de Recherche en Génomique Humaine
Robert Olaso - Centre National de Recherche en Génomique Humaine
Shahzad Ahmad
Philippe Amouyel
Claudine Berr
Anne Boland - CEA Paris-Saclay
Paola Bossu
Femke Bouwman
Jose Bras
Dominique Campion - Centre Hospitalier du Rouvray
Camille Charbonnier - Inserm
Jordi Clarimon
Antonio Daniele
Jean-François Dartigues
Stéphanie Debette
Jean-François Deleuze - Centre National de Recherche en Génomique Humaine
Nicola Denning - Inserm
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 - Commissariat à l'Énergie Atomique et aux Énergies Alternatives
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 - Inserm
Benedetta Nacmias
Gaël Nicolas - Inserm
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 - Normandie Université
Julie Williams
Aline Zarea - Normandie Université
Flora Alarcon - Centre National de la Recherche Scientifique
Dominique Campion - Centre Hospitalier du Rouvray
Grégory Nuel - Centre National de la Recherche Scientifique
Gaël Nicolas - Inserm
Publication Details: Genome Medicine, Vol.14(1)
Identifiers: 9933941209311
Academic Unit: Recherche hors université
Language: English
Resource Type: Journal article
Local Fields: hal-03971905