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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; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberly D.; Chan, Raymond C. K.; Chen, Ronald Y. L.; Chen, Eric Y. H.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Favero, Jurgen Del; DeLisi, Lynn E.; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Durmishi, Naser; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Farrell, Martilias S.; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedl, Marion; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Golimbet, Vera; Gopal, Srihari; Gratten, Jacob; Haan, Lieuwe de; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kahn, René S.; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Kähler, Anna K.; Laurent, Claudine; Keong, Jimmy Lee Chee; Lee, S. Hong; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Loughland, Carmel M.; Lubinski, Jan; Lönnqvist, Jouko; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Murphy, Kieran C.; Myin-Germeys, Inez; Müller-Myhsok, Bertram; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O’Callaghan, Eadbhard; O’Dushlaine, Colm; O’Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; Os, Jim Van; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Pejovic-Milovancevic, Milica; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Sigurdsson, Engilbert; Silagadze, Teimuraz; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; Smoller, Jordan W.; So, Hon-Cheong; Spencer, Chris C. A.; Stahl, Eli A.; Stefansson, Hreinn; Steinberg, Stacy; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Söderman, Erik; Thirumalai, Srinivas; Toncheva, Draga; Tosato, Sarah; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Stefansson, Kari; Visscher, Peter M.; Adolfsson, Rolf; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Børglum, Anders D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; Moran, Jennifer L.; Mortensen, Preben B.; Nöthen, Markus M.; Ophoff, Roel A.; Palotie, Aarno; Petryshen, Tracey L.; Posthuma, Danielle; Riley, Brien P.; Sham, Pak C.; Sklar, Pamela; Clair, David St; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Agbedjro, Deborah; Stahl, Daniel; Kapur, Shitij; Millgate, Edward; Kepinska, Adrianna; Kravariti, Eugenia; Ajnakina, Olesya; Alameda, Luis; Barnes, Thomas R. E.; Berardi, Domenico; Bonora, Elena; Camporesi, Sara; Cleusix, Martine; Conus, Philippe; Crespo-Facorro, Benedicto; D’Andrea, Giuseppe; Demjaha, Arsime; Do, Kim Q.; Doody, Gillian A.; Eap, Chin B.; Ferchiou, Aziz; Di Forti, Marta; Guidi, Lorenzo; Homman, Lina; Jenni, Raoul; Joyce, Eileen M.; Kassoumeri, Laura; Khadimallah, Inès; Lastrina, Ornella; Muratori, Roberto; Noyan, Handan; O’Neill, Francis A.; Pignon, Baptiste; Restellini, Romeo; Richard, Jean-Romain; Schürhoff, Franck; Španiel, Filip; Szöke, Andrei; Tarricone, Ilaria; Tortelli, Andrea; Üçok, Alp; Vázquez-Bourgon, Javier

Authors

Antonio F. Pardiñas

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

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 = 10 501) and individuals with non-TRS (n = 20 325). 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 85 490 participants (48 635 [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 (r 2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r 2 = 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. JAMA Psychiatry.

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, 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 Jan 12, 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
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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