@article{5b6cdaee3ec7403e8e19609e2654bab9,
title = "Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia",
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..",
author = "Pardi{\~n}as, {Antonio F.} and Smart, {Sophie E.} and Willcocks, {Isabella R.} and Holmans, {Peter A.} and Dennison, {Charlotte A.} and Lynham, {Amy J.} and Legge, {Sophie E.} and Baune, {Bernhard T.} and Bigdeli, {Tim B.} and Cairns, {Murray J.} and Aiden Corvin and Fanous, {Ayman H.} and Josef Frank and Brian Kelly and Andrew McQuillin and Ingrid Melle and Mortensen, {Preben B.} and Mowry, {Bryan J.} and Pato, {Carlos N.} and Sathish Periyasamy and Marcella Rietschel and Dan Rujescu and Carmen Simonsen and {St Clair}, David and Paul Tooney and Wu, {Jing Qin} and Andreassen, {Ole A.} and Kaarina Kowalec and Sullivan, {Patrick F.} and Murray, {Robin M.} and Owen, {Michael J.} and Maccabe, {James H.} and O'Donovan, {Michael C.} and Walters, {James T.R.} and Olesya Ajnakina and Luis Alameda and Barnes, {Thomas R.E.} and Domenico Berardi and Elena Bonora and Sara Camporesi and Martine Cleusix and Philippe Conus and Benedicto Crespo-Facorro and Giuseppe D'Andrea and Arsime Demjaha and Do, {Kim Q.} and Doody, {Gillian A.} and Eap, {Chin B.} and Aziz Ferchiou and {Di Forti}, Marta and Lorenzo Guidi and Lina Homman and Raoul Jenni and Joyce, {Eileen M.} and Laura Kassoumeri and In{\`e}s Khadimallah and Ornella Lastrina and Roberto Muratori and Handan Noyan and O'Neill, {Francis A.} and Baptiste Pignon and Romeo Restellini and Richard, {Jean Romain} and Franck Sch{\"u}rhoff and Filip {\v S}paniel and Andrei Sz{\"o}ke and Ilaria Tarricone and Andrea Tortelli and Alp {\"U}{\c c}ok and Javier V{\'a}zquez-Bourgon",
note = "Funding Information: Funding/Support: This work was supported by Medical Research Council Centre grant MR/ L010305/1, Medical Research Council Program grant MR/P005748/1, and Medical Research Council Project grants MR/L011794/1 and MC_PC_17212 to Cardiff University and by the National Centre for Mental Health, funded by the Welsh Government through Health and Care Research Wales. This work acknowledges the support of the Supercomputing Wales project, which is partially funded by the European Regional Development Fund via the Welsh Government. Dr Pardi{\~n}as was supported by an Academy of Medical Sciences Springboard Award (SBF005\1083). Dr Andreassen was supported by the Research Council of Norway (grants 283798, 262656, 248980, 273291, 248828, 248778, and 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, and the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (grant 847776). Dr Ajnakina was supported by an National Institute for Health Research postdoctoral fellowship (PDF-2018-11-ST2-020). Dr Joyce was supported by the University College London Hospitals/UCL University College London Biomedical Research Centre. Dr Kowalec received funding from the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme under the Marie Sk{\l}odowska-Curie grant agreement (793530) from the government of Canada Banting postdoctoral fellowship programme and the University of Manitoba. Dr Sullivan was supported by the Swedish Research Council (Vetenskapsr{\aa}det, D0886501), the European Union{\textquoteright}s Horizon 2020 programme (COSYN, 610307) and the US National Institute of Mental Health (U01 MH109528 and R01 MH077139). The Psychiatric Genomics Consortium was partly supported by the National Institute Of Mental Health (grants R01MH124873). The Sweden Schizophrenia Study was supported by the National Institute Of Mental Health (grant R01MH077139). The STRATA consortium was supported by a Stratified Medicine Programme grant to Dr MacCabe from the Medical Research Council (grant MR/L011794/1), which funded the research and supported Drs Pardi{\~n}as, Smart, Kassoumeri, Murray, Walters, and MacCabe. Dr Smart was supported by a Collaboration for Leadership in Applied Health Research and Care South London at King{\textquoteright}s College Hospital National Health Service Foundation Trust. The AESOP (US) cohort was funded by the UK Medical Research Council (grant G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community{\textquoteright}s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Genetics and Psychosis project (London, UK) cohort was funded by the UK National Institute of Health Research Specialist Biomedical Research Centre for Mental Health, South London and the Maudsley National Health Service Mental Health Foundation Trust (SLAM) and the Institute of Psychiatry, Psychology, and Neuroscience at King{\textquoteright}s College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community{\textquoteright}s Seventh Framework program (HEALTH-F2-2009-241909, project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (grants 320030_135736/1, 320030-120686, 324730-144064, 320030-173211, and 171804); the National Center of Competence in Research Synaptic Bases of Mental Diseases from the Swiss National Science Foundation (grant 51AU40_125759); and Fondation Alamaya. The Oslo (Norway) cohort was funded by the Research Council of Norway (grant 223273/F50, under the Centers of Excellence funding scheme, 300309, 283798) and the South-Eastern Norway Regional Health Authority (grants 2006233, 2006258, 2011085, 2014102, 2015088, and 2017-112). The Paris (France) cohort was funded by European Community{\textquoteright}s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (grant NU20-04-00393). The Santander (Spain) cohort was funded by the following grants to Dr Crespo-Facorro: Instituto de Salud Carlos III (grants FIS00/3095, PI020499, PI050427, and PI060507), Plan Nacional de Drogas Research (grant 2005-Orden sco/3246/2004), SENY Fundatio Research (grant 2005-0308007), Fundacion Marques de Valdecilla (grant A/02/07, API07/011) and Ministry of Economy and Competitiveness and the European Fund for Regional Development (grants SAF2016-76046-R and SAF2013-46292-R). The West London (UK) cohort was funded by The Wellcome Trust (grants 042025, 052247, and 064607). Funding Information: received grants from EraPerMEd as well as personal fees from AstraZeneca, Lundbeck, Pfizer, Takeda Pharmaceuticals, Servier, Bristol Myers Squibb, Otsuka, LivaNova, and Janssen-Cilag. Dr Andreassen has received grants from KG Jebsen Stiftelsen, South East Norway Health Authority, Research Council of Norway, and the European Union Horizon 2020 as well as personal fees from HealthLytix, Lundbeck, and Sunovion. Dr Sullivan has received research funding from Lundbeck as well as personal fees from Pfizer, Neumora, Element Genomics, and Roche; is a shareholder of Neumora; and serves on the advisory committee of Lundbeck. Dr Murray has received grants from Medical Research Council as well as personal fees from Janssen, Merck, Otsuka, Sunovian, and Lundbeck. Drs Owen, O{\textquoteright}Donovan, and Walters are investigators on a grant from Takeda Pharmaceuticals paid to Cardiff University; Dr Smart is employed by funds from this grant. Dr MacCabe has received research funding and nonfinancial support from Lundbeck. Dr O{\textquoteright}Donovan reported grants from the National Institutes of Health, UK Medical Research Council, Commission of the European Union, and Takeda Pharmaceuticals. Dr Walters has received grants from Medical Research Council, National Institutes of Health, and European Union 7th Framework Programme for Research, and Takeda Pharmaceuticals. Dr Barnes is a member of an advisory board for Gedeon Richter. Dr Camporesi has received grants from the Swiss National Centre Competence in Research. Dr Crespo-Facorro has received personal fees from Adamed, Mylan, Angelini, Janssen, Johnson & Johnson, Lundbeck, and Otsuka Pharmaceuticals. Dr Do has received grants from the Swiss National Science Foundation, and Boehringer Ingelheim and has a patent for EP19218841.5 pending. Dr Eap has received grants from the Swiss National Science Foundation and personal fees from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor Pharma, and Zeller. Dr Di Forti has received fees for educational seminars from Lundbeck and Janssen. Dr Sz{\"o}ke has received grants from the European Publisher Copyright: {\textcopyright} 2022 Pardi{\~n}as AF et al.",
year = "2022",
month = mar,
day = "1",
doi = "10.1001/jamapsychiatry.2021.3799",
language = "English",
volume = "79",
pages = "260--269",
journal = "JAMA Psychiatry",
issn = "2168-622X",
publisher = "American Medical Association",
number = "3",
}