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
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
- Function : Author
- PersonId : 933362
- ORCID : 0000-0002-7678-5065
- IdRef : 03566729X
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).
Domains
Human health and pathology
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