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 (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.

Assistance Publique Hôpitaux de Paris Hôpitaux Universitaires HMondor Département Médico Universitaire de Psychiatrie et d'Addictologie Fédération Hospitalo Universitaire de Médecine de Précision Créteil France

Baker Heart and Diabetes Institute Melbourne Australia

Center for Research and Innovation in Clinical Pharmaceutical Sciences Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Centre for Brain and Mental Health Research University of Newcastle Newcastle Australia

Centre For Public Health Institute Of Clinical Sciences Queens University Belfast Belfast United Kingdom

Centro de Investigacion Biomedica en Red de Salud Mental Spanish Network for Research in Mental Health Santander Spain

Centro de Investigacion Biomedica en Red de Salud Mental Spanish Network for Research in Mental Health Sevilla Spain

College of Pharmacy University of Manitoba Winnipeg Manitoba Canada

Department of Applied Neuroscience and Neuroimaging National Institute of Mental Health Klecany Czechia

Department of Behavioural Science and Health Institute of Epidemiology and Health Care University College London London United Kingdom

Department of Biomedical and Neuro motor Sciences Psychiatry Unit Alma Mater Studiorum Università di Bologna Bologna Italy

Department of Biostatistics and Health Informatics Institute of Psychiatry Psychology and Neuroscience King's College London University of London London United Kingdom

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim University of Heidelberg Heidelberg Mannheim Germany

Department of Genetics University of North Carolina Chapel Hill

Department of Medical and Surgical Sciences Bologna Transcultural Psychosomatic Team Alma Mater Studiorum University of Bologna Bologna Italy

Department of Medical Education University of Nottingham Faculty of Medicine and Health Sciences Nottingham United Kingdom

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medicine and Psychiatry School of Medicine University of Cantabria Santander Spain

Department of Psychiatry and Behavioral Sciences State University of New York Downstate Medical Center Brooklyn

Department of Psychiatry and Medical Psychology 3rd Faculty of Medicine Charles University Prague Czechia

Department of Psychiatry and the Behavioral Sciences State University of New York Downstate Medical Center Brooklyn

Department of Psychiatry and Zilkha Neurogenetics Institute Keck School of Medicine University of Southern California Los Angeles

Department of Psychiatry Icahn School of Medicine Mount Sinai Hospital New York New York

Department of Psychiatry Istanbul University Istanbul Turkey

Department of Psychiatry Melbourne Medical School The University of Melbourne Melbourne Australia

Department of Psychiatry University Hospital Marques de Valdecilla Instituto de Investigación Marques de Valdecilla Santander Spain

Department of Psychiatry University of Münster Münster Germany

Department of Psychiatry Veterans Affairs New York Harbor Healthcare System Brooklyn

Department of Psychosis Studies Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Department of Social and Welfare Studies Department of Behavioural Sciences and Learning Linköping University Linköping Sweden

Division of General Psychiatry Department of Psychiatry and Psychotherapy Medical University of Vienna Vienna Austria

Division of Mental Health and Addiction Institute of Clinical Medicine Oslo University Hospital Oslo Norway

Division of Psychiatry Imperial College London London United Kingdom

Early Intervention in Psychosis Advisory Unit for South East Norway Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Faculty of Social Sciences Department of Psychology Beykoz University Istanbul Turkey

Groupe Hospitalier Universitaire Psychiatrie Neurosciences Paris Pôle Psychiatrie Précarité Paris France

Hunter Medical Research Institute Newcastle Australia

Institute for Genomic Health State University of New York Downstate Medical Center Brooklyn

Institute of Medical Sciences University of Aberdeen Aberdeen United Kingdom

Institute of Pharmaceutical Sciences of Western Switzerland University of Geneva Geneva Switzerland

Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocio Departamento de Psiquiatria Universidad de Sevilla Sevilla Spain

Molecular Psychiatry Laboratory Division of Psychiatry University College London London United Kingdom

MRC Centre for Neuropsychiatric Genetics and Genomics Division of Psychological Medicine and Clinical Neurosciences School of Medicine Cardiff University Cardiff United Kingdom

National Centre for Register based Research Aarhus University Aarhus Denmark

Neuropsychiatric Genetics Research Group Department of Psychiatry Trinity College Dublin Dublin Ireland

Norwegian Centre for Mental Disorders Research Institute of Clinical Medicine University of Oslo Oslo Norway

Queensland Brain Institute The University of Queensland Brisbane Australia

Queensland Centre for Mental Health Research The University of Queensland Brisbane Australia

School of Biomedical Sciences and Pharmacy University of Newcastle Newcastle Australia

School of Medicine and Public Health The University of Newcastle Newcastle Australia

School of Pharmaceutical Sciences University of Geneva Geneva Switzerland

Social Genetics and Developmental Psychiatry Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

South London and Maudsley National Health Service Mental Health Foundation Trust London United Kingdom

The Florey Institute of Neuroscience and Mental Health The University of Melbourne Melbourne Australia

The Lundbeck Foundation Initiative for Integrative Psychiatric Research Aarhus Denmark

Treatment and Early Intervention in Psychosis Program Service of General Psychiatry Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

UCL Queen Square Institute of Neurology University College London London United Kingdom

Unit for Research in Schizophrenia Center for Psychiatric Neuroscience Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

Unit of Pharmacogenetics and Clinical Psychopharmacology Centre for Psychiatric Neuroscience Department of Psychiatry Lausanne University Hospital University of Lausanne Prilly Switzerland

University Clinic and Outpatient Clinic for Psychiatry Psychotherapy and Psychosomatics Martin Luther University of Halle Wittenberg Halle Germany

University Paris Est Créteil Institut national de la santé et de la recherche médicale Mondor Institute for Biomedical Research Translational Neuropsychiatry Fondation FondaMental Créteil France

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