Antonio F. Pardiñas
Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia
Pardiñas, Antonio F.; Smart, Sophie E.; Willcocks, Isabella R.; Holmans, Peter A.; Dennison, Charlotte A.; Lynham, Amy J.; Legge, Sophie E.; Baune, Bernhard T.; Bigdeli, Tim B.; Cairns, Murray J.; Corvin, Aiden; Fanous, Ayman H.; Frank, Josef; Kelly, Brian; McQuillin, Andrew; Melle, Ingrid; Mortensen, Preben B.; Mowry, Bryan J.; Pato, Carlos N.; Periyasamy, Sathish; Rietschel, Marcella; Rujescu, Dan; Simonsen, Carmen; St Clair, David; Tooney, Paul; Wu, Jing Qin; Andreassen, Ole A.; Kowalec, Kaarina; Sullivan, Patrick F.; Murray, Robin M.; Owen, Michael J.; MacCabe, James H.; O’Donovan, Michael C.; Walters, James T. R.; Ripke, Stephan; Neale, Benjamin M.; Farh, Kai-How; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A .; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Black, Donald W.; Bruggeman, Richard; B...
Authors
Sophie E. Smart
Isabella R. Willcocks
Peter A. Holmans
Charlotte A. Dennison
Amy J. Lynham
Sophie E. Legge
Bernhard T. Baune
Tim B. Bigdeli
Murray J. Cairns
Aiden Corvin
Ayman H. Fanous
Josef Frank
Brian Kelly
Andrew McQuillin
Ingrid Melle
Preben B. Mortensen
Bryan J. Mowry
Carlos N. Pato
Sathish Periyasamy
Marcella Rietschel
Dan Rujescu
Carmen Simonsen
David St Clair
Paul Tooney
Jing Qin Wu
Ole A. Andreassen
Kaarina Kowalec
Patrick F. Sullivan
Robin M. Murray
Michael J. Owen
James H. MacCabe
Michael C. O’Donovan
James T. R. Walters
Stephan Ripke
Benjamin M. Neale
Kai-How Farh
Phil Lee
Brendan Bulik-Sullivan
David A. Collier
Hailiang Huang
Tune H. Pers
Ingrid Agartz
Esben Agerbo
Margot Albus
Madeline Alexander
Farooq Amin
Silviu A. Bacanu
Martin Begemann
Richard A . Belliveau
Judit Bene
Sarah E. Bergen
Elizabeth Bevilacqua
Donald W. Black
Richard Bruggeman
Nancy G. Buccola
Randy L. Buckner
William Byerley
Wiepke Cahn
Guiqing Cai
Dominique Campion
Rita M. Cantor
Vaughan J. Carr
Noa Carrera
Stanley V. Catts
Kimberly D. Chambert
Raymond C. K. Chan
Ronald Y. L. Chen
Eric Y. H. Chen
Wei Cheng
Eric F. C. Cheung
Siow Ann Chong
C. Robert Cloninger
David Cohen
Nadine Cohen
Paul Cormican
Nick Craddock
James J. Crowley
David Curtis
Michael Davidson
Kenneth L. Davis
Franziska Degenhardt
Jurgen Del Favero
Lynn E. DeLisi
Ditte Demontis
Dimitris Dikeos
Timothy Dinan
Srdjan Djurovic
Gary Donohoe
Elodie Drapeau
Jubao Duan
Frank Dudbridge
Naser Durmishi
Peter Eichhammer
Johan Eriksson
Valentina Escott-Price
Laurent Essioux
Martilias S. Farrell
Lude Franke
Robert Freedman
Nelson B. Freimer
Marion Friedl
Joseph I. Friedman
Menachem Fromer
Giulio Genovese
Lyudmila Georgieva
Elliot S. Gershon
Ina Giegling
Paola Giusti-Rodríguez
Stephanie Godard
Jacqueline I. Goldstein
Vera Golimbet
Srihari Gopal
Jacob Gratten
Lieuwe de Haan
Christian Hammer
Marian L. Hamshere
Mark Hansen
Thomas Hansen
Vahram Haroutunian
Annette M. Hartmann
Frans A. Henskens
Stefan Herms
Joel N. Hirschhorn
Per Hoffmann
Andrea Hofman
Mads V. Hollegaard
David M. Hougaard
Masashi Ikeda
Inge Joa
Antonio Julià
René S. Kahn
Luba Kalaydjieva
Sena Karachanak-Yankova
Juha Karjalainen
David Kavanagh
Matthew C. Keller
James L. Kennedy
Andrey Khrunin
Yunjung Kim
Janis Klovins
James A. Knowles
Bettina Konte
Vaidutis Kucinskas
Zita Ausrele Kucinskiene
Hana Kuzelova-Ptackova
Anna K. Kähler
Claudine Laurent
Jimmy Lee Chee Keong
S. Hong Lee
Bernard Lerer
Miaoxin Li
Tao Li
Kung-Yee Liang
Jeffrey Lieberman
Svetlana Limborska
Carmel M. Loughland
Jan Lubinski
Jouko Lönnqvist
Milan Macek
Patrik K. E. Magnusson
Brion S. Maher
Wolfgang Maier
Jacques Mallet
Sara Marsal
Manuel Mattheisen
Morten Mattingsdal
Robert W. McCarley
Colm McDonald
Andrew M. McIntosh
Sandra Meier
Carin J. Meijer
Bela Melegh
Ingrid Melle
Raquelle I. Mesholam-Gately
Andres Metspalu
Patricia T. Michie
Lili Milani
Vihra Milanova
Younes Mokrab
Derek W. Morris
Ole Mors
Kieran C. Murphy
Inez Myin-Germeys
Bertram Müller-Myhsok
Mari Nelis
Igor Nenadic
Deborah A. Nertney
Gerald Nestadt
Kristin K. Nicodemus
Liene Nikitina-Zake
Laura Nisenbaum
Annelie Nordin
Eadbhard O’Callaghan
Colm O’Dushlaine
F. Anthony O’Neill
Sang-Yun Oh
Ann Olincy
Line Olsen
Jim Van Os
Christos Pantelis
George N. Papadimitriou
Sergi Papiol
Elena Parkhomenko
Michele T. Pato
Tiina Paunio
Milica Pejovic-Milovancevic
Diana O. Perkins
Olli Pietiläinen
Jonathan Pimm
Andrew J. Pocklington
John Powell
Alkes Price
Ann E. Pulver
Shaun M. Purcell
Digby Quested
Henrik B. Rasmussen
Abraham Reichenberg
Mark A. Reimers
Alexander L. Richards
Joshua L. Roffman
Panos Roussos
Douglas M. Ruderfer
Veikko Salomaa
Alan R. Sanders
Ulrich Schall
Christian R. Schubert
Thomas G. Schulze
Sibylle G. Schwab
Edward M. Scolnick
Rodney J. Scott
Larry J. Seidman
Jianxin Shi
Engilbert Sigurdsson
Teimuraz Silagadze
Jeremy M. Silverman
Kang Sim
Petr Slominsky
Jordan W. Smoller
Hon-Cheong So
Chris C. A. Spencer
Eli A. Stahl
Hreinn Stefansson
Stacy Steinberg
Elisabeth Stogmann
Richard E. Straub
Eric Strengman
Jana Strohmaier
T. Scott Stroup
Mythily Subramaniam
Jaana Suvisaari
Dragan M. Svrakic
Jin P. Szatkiewicz
Erik Söderman
Srinivas Thirumalai
Draga Toncheva
Sarah Tosato
Juha Veijola
John Waddington
Dermot Walsh
Dai Wang
Qiang Wang
Bradley T. Webb
Mark Weiser
Dieter B. Wildenauer
Nigel M. Williams
Stephanie Williams
Stephanie H. Witt
Aaron R. Wolen
Emily H. M. Wong
Brandon K. Wormley
Hualin Simon Xi
Clement C. Zai
Xuebin Zheng
Fritz Zimprich
Naomi R. Wray
Kari Stefansson
Peter M. Visscher
Rolf Adolfsson
Douglas H. R. Blackwood
Elvira Bramon
Joseph D. Buxbaum
Anders D. Børglum
Sven Cichon
Ariel Darvasi
Enrico Domenici
Hannelore Ehrenreich
Tõnu Esko
Pablo V. Gejman
Michael Gill
Hugh Gurling
Christina M. Hultman
Nakao Iwata
Assen V. Jablensky
Erik G. Jönsson
Kenneth S. Kendler
George Kirov
Jo Knight
Todd Lencz
Douglas F. Levinson
Qingqin S. Li
Jianjun Liu
Anil K. Malhotra
Steven A. McCarroll
Jennifer L. Moran
Preben B. Mortensen
Markus M. Nöthen
Roel A. Ophoff
Aarno Palotie
Tracey L. Petryshen
Danielle Posthuma
Brien P. Riley
Pak C. Sham
Pamela Sklar
David St Clair
Daniel R. Weinberger
Jens R. Wendland
Thomas Werge
Mark J. Daly
Deborah Agbedjro
Daniel Stahl
Shitij Kapur
Edward Millgate
Adrianna Kepinska
Eugenia Kravariti
Olesya Ajnakina
Luis Alameda
Thomas R. E. Barnes
Domenico Berardi
Elena Bonora
Sara Camporesi
Martine Cleusix
Philippe Conus
Benedicto Crespo-Facorro
Giuseppe D’Andrea
Arsime Demjaha
Kim Q. Do
Gillian A. Doody
Chin B. Eap
Aziz Ferchiou
Marta Di Forti
Lorenzo Guidi
Lina Homman
Raoul Jenni
Eileen M. Joyce
Laura Kassoumeri
Inès Khadimallah
Ornella Lastrina
Roberto Muratori
Handan Noyan
Francis A. O’Neill
Baptiste Pignon
Romeo Restellini
Jean-Romain Richard
Franck Schürhoff
Filip Španiel
Andrei Szöke
Ilaria Tarricone
Andrea Tortelli
Alp Üçok
Javier Vázquez-Bourgon
Abstract
Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10501) and individuals with non-TRS (n = 20325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85490 participants (48635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P =.001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P =.04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.
Citation
Pardiñas, A. F., Smart, S. E., Willcocks, I. R., Holmans, P. A., Dennison, C. A., Lynham, A. J., …Vázquez-Bourgon, J. (2022). Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia. JAMA Psychiatry, 79(3), 260-269. https://doi.org/10.1001/jamapsychiatry.2021.3799
Journal Article Type | Article |
---|---|
Acceptance Date | Nov 2, 2021 |
Online Publication Date | Jan 12, 2022 |
Publication Date | Mar 1, 2022 |
Deposit Date | Jan 14, 2022 |
Publicly Available Date | Jan 14, 2022 |
Journal | JAMA Psychiatry |
Print ISSN | 2168-622X |
Electronic ISSN | 2168-6238 |
Publisher | American Medical Association |
Peer Reviewed | Peer Reviewed |
Volume | 79 |
Issue | 3 |
Pages | 260-269 |
DOI | https://doi.org/10.1001/jamapsychiatry.2021.3799 |
Keywords | Psychiatry and Mental health |
Public URL | https://nottingham-repository.worktribe.com/output/7229725 |
Publisher URL | https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2787666 |
Additional Information | Authors on behalf of the Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). University of Nottingham author: Professor Gillian A. Doody. (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium) |
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