Polygenic risk and hazard scores for Alzheimer's disease prediction - Sorbonne Université
Journal Articles Annals of Clinical and Translational Neurology Year : 2019

Polygenic risk and hazard scores for Alzheimer's disease prediction

Ganna Leonenko (1) , Rebecca Sims (1) , Maryam Shoai (2) , Aura Frizzati (1) , Paola Bossù (3) , Gianfranco Spalletta (3) , Nick C Fox (2) , Julie Williams (1) , John Hardy (2) , Valentina Escott-Price (1) , Magda Tsolaki , David Craig , Despoina Avramidou , Antonia Germanou , Maria Koutroumani , Olymbia Gkatzima , Harald Hampel (4) , Patrick G Kehoe , Seth Love , David C Rubinsztein , Lutz Frölich , Bernadette Mcguinness , Janet A Johnston , Peter Passmore , Dmitriy Drichel , Martin Rossor , Jonathan M Schott , Jason D Warren , Jose Bras , Rita Guerreiro , Amit Kawalia Joseph T Hughes , Yogen Patel , Michelle K Lupton , Petra Proitsi , John Powell , John S K Kauwe , Michelangelo Mancuso , Ubaldo Bonuccelli , James Uphill , Elizabeth Fisher , Carlo Masullo , Hilkka Soininen , Gina Bisceglio , Li Ma , Dennis W Dickson , Neill R Graff-Radford , Minerva M Carrasquillo , Steven G Younkin , Sandro Sorbi , Makrina Daniilidou , Angela Hodges , Daniela Galimberti , Elio Scarpini , Martin Scherer , Oliver Peters , Alfredo Ramirez , Markus Leber , Sabrina Pichler , Manuel Mayhaus , Wei Gu , Matthias Riemenschneider , Jens Wiltfang , Reinhard Heun , Heike Kölsch , Johannes Kornhuber , Isabella Heuser , Dan Rujescu , Annette M Hartmann , Ina Giegling , Michael Hüll , Simon Lovestone , Carlos Cruchaga , John Morris , Kevin Mayo , Thomas Feulner , Rebecca Sussams , Clive Holmes , David Mann , Stuart Pickering-Brown , Nigel M Hooper , Andrew Mcquillin , Gill Livingston , Nicholas J Bass , Maria Vronskaya , Taniesha Morgan , Nicola Denning , Thomas D Cushion , Lesley Jones , Rachel Marshall , Alun Meggy , Georgina Menzies , Detelina Grozeva , Michael C O'Donovan , Michael J Owen , Peter A Holmans , Francesca Salani , Giancarlo Russo , Wolfgang Maier , Frank Jessen , H-Erich Wichmann , Kevin Morgan , Alison M Goate , Bruno Vellas , Emma Vardy , Susanne Moebus , Karl-Heinz Jöckel , Martin Dichgans , Norman Klopp , James Turton , Jenny Lord , Kristelle Brown , Christopher Medway , Markus M Nöthen , Per Hoffmann , Antonio Daniele , Anthony Bayer , John Gallacher , Hendrik van Den Bussche , Carol Brayne , Steffi Riedel-Heller , John F Powell , Ammar Al-Chalabi , Christopher E Shaw , Iwona Kloszewska , Pau Pastor , Monica Diez-Fairen , Aoibhinn Lynch , Brian Lawlor , Michael Gill , Eliecer Coto , Victoria Alvarez , Andrew B Singleton , John Collinge , Simon Mead , Natalie Ryan , Benedetta Nacmias , Sara Ortega-Cubero , Eloy Rodriguez-Rodriguez , Pascual Sanchez-Juan , Jacob Shofany , Nerisa Banaj , Valentina Ciullo , Eleonora Sacchinelli , Robert Clarke , a David Smith , Donald Warden , Yoav Ben-Shlomo , Chiara Cupidi , Raffaele Giovanni Maletta , Amalia Cecilia Bruni , Maura Gallo , Denise Harold , Roberta Cecchetti , Patrizia Mecocci , Virginia Boccardi , Nick Warner , Gordon Wilcock , Panagiotis Deloukas , Rhian Gwilliam , Chris Corcoran , Joann Tschanz , Ron Munger
Ganna Leonenko
Rebecca Sims
  • Function : Author
Aura Frizzati
  • Function : Author
Magda Tsolaki
  • Function : Author
David Craig
  • Function : Author
Despoina Avramidou
  • Function : Author
Antonia Germanou
  • Function : Author
Maria Koutroumani
  • Function : Author
Olymbia Gkatzima
  • Function : Author
Patrick G Kehoe
  • Function : Author
Seth Love
  • Function : Author
David C Rubinsztein
  • Function : Author
Lutz Frölich
  • Function : Author
Bernadette Mcguinness
  • Function : Author
Janet A Johnston
  • Function : Author
Peter Passmore
  • Function : Author
Dmitriy Drichel
  • Function : Author
Martin Rossor
  • Function : Author
Jonathan M Schott
  • Function : Author
Jason D Warren
  • Function : Author
Jose Bras
  • Function : Author
Rita Guerreiro
  • Function : Author
Amit Kawalia Joseph T Hughes
  • Function : Author
Yogen Patel
  • Function : Author
Michelle K Lupton
  • Function : Author
Petra Proitsi
  • Function : Author
John Powell
  • Function : Author
John S K Kauwe
  • Function : Author
Michelangelo Mancuso
  • Function : Author
Ubaldo Bonuccelli
  • Function : Author
James Uphill
  • Function : Author
Elizabeth Fisher
  • Function : Author
Carlo Masullo
  • Function : Author
Hilkka Soininen
  • Function : Author
Gina Bisceglio
  • Function : Author
Li Ma
  • Function : Author
Dennis W Dickson
  • Function : Author
Neill R Graff-Radford
  • Function : Author
Minerva M Carrasquillo
  • Function : Author
Steven G Younkin
  • Function : Author
Sandro Sorbi
  • Function : Author
Makrina Daniilidou
  • Function : Author
Angela Hodges
  • Function : Author
Daniela Galimberti
  • Function : Author
Elio Scarpini
  • Function : Author
Martin Scherer
  • Function : Author
Oliver Peters
  • Function : Author
Alfredo Ramirez
  • Function : Author
Markus Leber
  • Function : Author
Sabrina Pichler
  • Function : Author
Manuel Mayhaus
  • Function : Author
Wei Gu
  • Function : Author
Matthias Riemenschneider
  • Function : Author
Jens Wiltfang
  • Function : Author
Reinhard Heun
  • Function : Author
Heike Kölsch
  • Function : Author
Johannes Kornhuber
  • Function : Author
Isabella Heuser
  • Function : Author
Dan Rujescu
  • Function : Author
Annette M Hartmann
  • Function : Author
Ina Giegling
  • Function : Author
Michael Hüll
  • Function : Author
Simon Lovestone
  • Function : Author
Carlos Cruchaga
  • Function : Author
John Morris
  • Function : Author
Kevin Mayo
  • Function : Author
Thomas Feulner
  • Function : Author
Rebecca Sussams
  • Function : Author
Clive Holmes
  • Function : Author
David Mann
  • Function : Author
Stuart Pickering-Brown
  • Function : Author
Nigel M Hooper
  • Function : Author
Andrew Mcquillin
  • Function : Author
Gill Livingston
  • Function : Author
Nicholas J Bass
  • Function : Author
Maria Vronskaya
  • Function : Author
Taniesha Morgan
  • Function : Author
Nicola Denning
  • Function : Author
Thomas D Cushion
  • Function : Author
Lesley Jones
  • Function : Author
Rachel Marshall
  • Function : Author
Alun Meggy
  • Function : Author
Georgina Menzies
  • Function : Author
Detelina Grozeva
  • Function : Author
Michael C O'Donovan
  • Function : Author
Michael J Owen
  • Function : Author
Peter A Holmans
  • Function : Author
Francesca Salani
  • Function : Author
Giancarlo Russo
  • Function : Author
Wolfgang Maier
  • Function : Author
Frank Jessen
  • Function : Author
H-Erich Wichmann
  • Function : Author
Kevin Morgan
  • Function : Author
Alison M Goate
  • Function : Author
Bruno Vellas
Emma Vardy
  • Function : Author
Susanne Moebus
  • Function : Author
Karl-Heinz Jöckel
  • Function : Author
Martin Dichgans
  • Function : Author
Norman Klopp
  • Function : Author
James Turton
  • Function : Author
Jenny Lord
  • Function : Author
Kristelle Brown
  • Function : Author
Christopher Medway
  • Function : Author
Markus M Nöthen
  • Function : Author
Per Hoffmann
  • Function : Author
Antonio Daniele
  • Function : Author
Anthony Bayer
  • Function : Author
John Gallacher
  • Function : Author
Hendrik van Den Bussche
  • Function : Author
Carol Brayne
  • Function : Author
Steffi Riedel-Heller
  • Function : Author
John F Powell
  • Function : Author
Ammar Al-Chalabi
  • Function : Author
Christopher E Shaw
  • Function : Author
Iwona Kloszewska
  • Function : Author
Pau Pastor
  • Function : Author
Monica Diez-Fairen
  • Function : Author
Aoibhinn Lynch
  • Function : Author
Brian Lawlor
  • Function : Author
Michael Gill
  • Function : Author
Eliecer Coto
  • Function : Author
Victoria Alvarez
  • Function : Author
Andrew B Singleton
  • Function : Author
John Collinge
  • Function : Author
Simon Mead
  • Function : Author
Natalie Ryan
  • Function : Author
Benedetta Nacmias
  • Function : Author
Sara Ortega-Cubero
  • Function : Author
Eloy Rodriguez-Rodriguez
  • Function : Author
Pascual Sanchez-Juan
  • Function : Author
Jacob Shofany
  • Function : Author
Nerisa Banaj
  • Function : Author
Valentina Ciullo
  • Function : Author
Eleonora Sacchinelli
  • Function : Author
Robert Clarke
  • Function : Author
a David Smith
  • Function : Author
Donald Warden
  • Function : Author
Yoav Ben-Shlomo
  • Function : Author
Chiara Cupidi
  • Function : Author
Raffaele Giovanni Maletta
  • Function : Author
Amalia Cecilia Bruni
  • Function : Author
Maura Gallo
  • Function : Author
Denise Harold
  • Function : Author
Roberta Cecchetti
  • Function : Author
Patrizia Mecocci
  • Function : Author
Virginia Boccardi
  • Function : Author
Nick Warner
  • Function : Author
Gordon Wilcock
  • Function : Author
Panagiotis Deloukas
  • Function : Author
Rhian Gwilliam
  • Function : Author
Chris Corcoran
  • Function : Author
Joann Tschanz
  • Function : Author
Ron Munger
  • Function : Author

Abstract

Abstract Objective Genome‐wide association studies ( GWAS ) have identified over 30 susceptibility loci associated with Alzheimer's disease ( AD ). Using AD GWAS data from the International Genomics of Alzheimer's Project ( IGAP ), Polygenic Risk Score ( PRS ) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score ( PHS ) is able to quantify individuals with age‐specific genetic risk for AD . The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS . Methods Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS , was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium ( GERAD ). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS . This was repeated using varying SNP s P ‐value thresholds for disease association. Results Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNP s were preselected for association to AD at P ≤ 0.001. The strongest effect ( B = 0.28, SE = 0.04, P = 2.5 × 10 −12 ) was observed for PRS based upon genome‐wide significant SNP s ( P ≤ 5 × 10 −8 ). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation Both PRS and PHS can be used to predict an age‐specific risk for developing AD . The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNP s were selected based upon AD GWAS case/control P ≤ 10 −3 , we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNP s are selected for association with AD risk at P > 10 −3 , the age‐specific risk prediction results are not significant for either PRS or PHS . However PHS could be more advantageous than PRS of age specific AD risk predictions when SNP s are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).
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Dates and versions

hal-04444983 , version 1 (07-02-2024)

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Ganna Leonenko, Rebecca Sims, Maryam Shoai, Aura Frizzati, Paola Bossù, et al.. Polygenic risk and hazard scores for Alzheimer's disease prediction. Annals of Clinical and Translational Neurology, 2019, 6 (3), pp.456-465. ⟨10.1002/acn3.716⟩. ⟨hal-04444983⟩
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