Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Article Article scientifique Article Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia eng 2022-03-01 author Pardiñas Antonio F MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Smart Sophie E 0000-0002-6709-5425 MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.,Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. author Willcocks Isabella R 0000-0002-3568-5236 MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Holmans Peter A MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Dennison Charlotte A 0000-0002-7493-2041 MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Lynham Amy J 0000-0002-3189-6888 MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Legge Sophie E MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Baune Bernhard T Department of Psychiatry, University of Münster, Münster, Germany.,Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia.,The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia. author Bigdeli Tim B Department of Psychiatry and the Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn.,Institute for Genomic Health, State University of New York Downstate Medical Center, Brooklyn.,Department of Psychiatry, Veterans Affairs New York Harbor Healthcare System, Brooklyn. author Cairns Murray J School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.,Centre for Brain and Mental Health Research, University of Newcastle, Newcastle, Australia.,Hunter Medical Research Institute, Newcastle, Australia. author Corvin Aiden 0000-0001-6717-4089 Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. author Fanous Ayman H Department of Psychiatry and the Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn.,Institute for Genomic Health, State University of New York Downstate Medical Center, Brooklyn. author Frank Josef Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany. author Kelly Brian Christopher School of Medicine & Public Health, The University of Newcastle, Newcastle, Australia. 661006 author McQuillin Andrew Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom. author Melle Ingrid Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Mental Health and Addiction, Institute of Clinical Medicine, Oslo University Hospital, Oslo, Norway. author Mortensen Preben B National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.,The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. author Mowry Bryan J 0000-0002-4115-5645 Queensland Brain Institute, The University of Queensland, Brisbane, Australia.,Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Australia. author Pato Carlos N Department of Psychiatry and 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.,Institute for Genomic Health, State University of New York Downstate Medical Center, Brooklyn. author Periyasamy Sathish 0000-0002-8132-5717 Queensland Brain Institute, The University of Queensland, Brisbane, Australia.,Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Australia. author Rietschel Marcella Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany. author Rujescu Dan University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany.,Division of General Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria. author Simonsen Carmen Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Early Intervention in Psychosis Advisory Unit for South-East Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. author St Clair David Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom. author Tooney Paul School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.,Hunter Medical Research Institute, Newcastle, Australia. author Wu Jing Qin Baker Heart and Diabetes Institute, Melbourne, Australia. author Andreassen Ole A Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Mental Health and Addiction, Institute of Clinical Medicine, Oslo University Hospital, Oslo, Norway. author Kowalec Kaarina College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. author Sullivan Patrick F Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Psychiatry, Icahn School of Medicine, Mount Sinai Hospital, New York, New York.,Department of Genetics, University of North Carolina, Chapel Hill. author Murray Robin M 0000-0003-0829-0519 Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. author Owen Michael J MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author MacCabe James H 0000-0002-6754-1018 Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. author O'Donovan Michael C MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Walters James T R MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. author Ajnakina Olesya Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, University of London, London, United Kingdom.,Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London, London, United Kingdom. author Alameda Luis 0000-0002-8621-2885 Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.,Centro de Investigacion Biomedica en Red de Salud Mental, Spanish Network for Research in Mental Health, Sevilla, Spain.,Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Departamento de Psiquiatria, Universidad de Sevilla, Sevilla, Spain.,Treatment and Early Intervention in Psychosis Program, Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. author Barnes Thomas R E Division of Psychiatry, Imperial College London, London, United Kingdom. author Berardi Domenico Department of Biomedical and Neuro-motor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy. author Bonora Elena Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team, Alma Mater Studiorum, University of Bologna, Bologna, Italy. author Camporesi Sara 0009-0005-3204-5099 Treatment and Early Intervention in Psychosis Program, Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.,Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. 426448 author Cleusix Martine Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. author Conus Philippe Treatment and Early Intervention in Psychosis Program, Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. author Crespo-Facorro Benedicto Centro de Investigacion Biomedica en Red de Salud Mental, Spanish Network for Research in Mental Health, Sevilla, Spain.,Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Departamento de Psiquiatria, Universidad de Sevilla, Sevilla, Spain. author D'Andrea Giuseppe 0000-0001-7014-645X Department of Biomedical and Neuro-motor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy. author Demjaha Arsime 0000-0002-1870-6410 Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. author Do Kim Q 0000-0003-1968-1646 Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. author Doody Gillian A 0000-0002-3494-438X Department of Medical Education, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom. author Eap Chin Bin Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland.,School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.,Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland. 648560 author Ferchiou Mohamed Aziz 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. 804265 author Di Forti Marta Social Genetics and Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.,South London and Maudsley National Health Service Mental Health Foundation Trust, London, United Kingdom. author Guidi Lorenzo Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team, Alma Mater Studiorum, University of Bologna, Bologna, Italy. author Homman Lina Department of Social and Welfare Studies, Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.,Centre For Public Health, Institute Of Clinical Sciences, Queens University Belfast, Belfast, United Kingdom. author Jenni Raoul 0000-0001-6479-5381 Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. 583450 author Joyce Eileen M UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. author Kassoumeri Laura Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. author Khadimallah Inès Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. author Lastrina Ornella Department of Biomedical and Neuro-motor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy. author Muratori Roberto Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team, Alma Mater Studiorum, University of Bologna, Bologna, Italy. author Noyan Handan 0009-0006-4160-6254 Faculty of Social Sciences, Department of Psychology, Beykoz University, Istanbul, Turkey. author O'Neill Francis A Centre For Public Health, Institute Of Clinical Sciences, Queens University Belfast, Belfast, United Kingdom. author Pignon Baptiste 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.,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. author Restellini Romeo Treatment and Early Intervention in Psychosis Program, Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.,Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. 642332 author Richard Jean-Romain 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. author Schürhoff Franck 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.,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. author Španiel Filip Department of Applied Neuroscience and Neuroimaging, National Institute of Mental Health, Klecany, Czechia.,Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czechia. author Szöke Andrei 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.,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. author Tarricone Ilaria Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team, Alma Mater Studiorum, University of Bologna, Bologna, Italy. author Tortelli Andrea 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.,Groupe Hospitalier Universitaire Psychiatrie Neurosciences Paris, Pôle Psychiatrie Précarité, Paris, France. author Üçok Alp Department of Psychiatry, Istanbul University, Istanbul, Turkey. author Vázquez-Bourgon Javier Department of Psychiatry, University Hospital Marques de Valdecilla-Instituto de Investigación Marques de Valdecilla, Santander, Spain.,Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander, Spain.,Centro de Investigacion Biomedica en Red de Salud Mental, Spanish Network for Research in Mental Health, Santander, Spain. Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) 260-269 10.1001/jamapsychiatry.2021.3799 35019943 2168-622X PMC8756361 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. Female Genetic Predisposition to Disease / genetics Genome-Wide Association Study Humans Male Multifactorial Inheritance / genetics Psychotic Disorders / drug therapy Schizophrenia / diagnosis Schizophrenia / drug therapy Schizophrenia / genetics Dewey 615 Wellcome Trust 052247 United Kingdom NIMH NIH HHS R01 MH104964 United States Medical Research Council G0500817 United Kingdom Medical Research Council MR/L011794/1 United Kingdom Medical Research Council MR/L010305/1 United Kingdom Medical Research Council G0801418 United Kingdom NIMH NIH HHS U01 MH109528 United States NIMH NIH HHS R01 MH124873 United States Wellcome Trust 042025 United Kingdom NIMH NIH HHS R01 MH123451 United States Medical Research Council MR/P005748/1 United Kingdom NIMH NIH HHS R01 MH077139 United States Department of Health PDF-2018-11-ST2-020 United Kingdom Wellcome Trust United Kingdom Medical Research Council MC_PC_17212 United Kingdom Academy of Medical Sciences SBF005\1083 31 Section des sciences pharmaceutiques 17 false JAMA psychiatry 79 3 01c84982-b7d0-4c16-a599-7e2fb9a1e075 Article (Published version) Public jamapsychiatry_pardias_2022_oi_2100.pdf 1086569 application/pdf CC BY 36d33900d8fbf7de958e87110ebeb4809bb2995962dacd931846996f2462ec72 93e2704a-318e-44de-a6d1-5eb37474d94d Appendix Public jamapsychiatry-e213799-s001.pdf 1070630 application/pdf 26d26b4cf7d958bec47e64c2ee386c2a4af342ce1d9643ffe470dba3053ad8d6 5057fe61-b4d7-41dc-acd4-58b7ca4a6c8c Appendix Public jamapsychiatry-e213799-s002.pdf 151052 application/pdf b25f4b4c5ebf92fcdc10c9921beb21dd1782c459825976aee09c8ed22d0f0a5c openAccess Faculté des sciences / Section des sciences pharmaceutiques

Title	Published in	Year	Views	Downloads

Clinical predictors of antipsychotic treatment resistance: Development and internal validation of a prognostic prediction model by the STRATA-G consortium	Schizophrenia research	2022	45	142
Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia	JAMA psychiatry	2022	36	151

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Ferchiou, Mohamed Aziz