Antonio F Pardiñas1, Sophie E Smart1,2, Isabella R Willcocks1, Peter A Holmans1, Charlotte A Dennison1, Amy J Lynham1, Sophie E Legge1, Bernhard T Baune3,4,5, Tim B Bigdeli6,7,8, Murray J Cairns9,10,11, Aiden Corvin12, Ayman H Fanous6,7, Josef Frank13, Brian Kelly14, Andrew McQuillin15, Ingrid Melle16,17, Preben B Mortensen18,19, Bryan J Mowry20,21, Carlos N Pato22,23,7, Sathish Periyasamy20,21, Marcella Rietschel13, Dan Rujescu24,25, Carmen Simonsen16,26, David St Clair27, Paul Tooney9,11, Jing Qin Wu28, Ole A Andreassen16,17, Kaarina Kowalec29,30, Patrick F Sullivan30,31,32, Robin M Murray2, Michael J Owen1, James H MacCabe2, Michael C O'Donovan1, James T R Walters1, Olesya Ajnakina33,34, Luis Alameda2,35,36,37, Thomas R E Barnes38, Domenico Berardi39, Elena Bonora40, Sara Camporesi37,41, Martine Cleusix41, Philippe Conus37, Benedicto Crespo-Facorro35,36, Giuseppe D'Andrea39, Arsime Demjaha2, Kim Q Do41, Gillian A Doody42, Chin B Eap43,44,45,46, Aziz Ferchiou47, Marta Di Forti48,49, Lorenzo Guidi40, Lina Homman50,51, Raoul Jenni41, Eileen M Joyce52, Laura Kassoumeri2, Inès Khadimallah41, Ornella Lastrina39, Roberto Muratori40, Handan Noyan53, Francis A O'Neill51, Baptiste Pignon47,54, Romeo Restellini37,41, Jean-Romain Richard47, Franck Schürhoff47,54, Filip Španiel55,56, Andrei Szöke47,54, Ilaria Tarricone40, Andrea Tortelli47,57, Alp Üçok58, Javier Vázquez-Bourgon59,60,61. 1. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom. 2. Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. 3. Department of Psychiatry, University of Münster, Münster, Germany. 4. Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia. 5. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia. 6. Department of Psychiatry and the Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn. 7. Institute for Genomic Health, State University of New York Downstate Medical Center, Brooklyn. 8. Department of Psychiatry, Veterans Affairs New York Harbor Healthcare System, Brooklyn. 9. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia. 10. Centre for Brain and Mental Health Research, University of Newcastle, Newcastle, Australia. 11. Hunter Medical Research Institute, Newcastle, Australia. 12. Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 13. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany. 14. School of Medicine & Public Health, The University of Newcastle, Newcastle, Australia. 15. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom. 16. Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 17. Division of Mental Health and Addiction, Institute of Clinical Medicine, Oslo University Hospital, Oslo, Norway. 18. National Centre for Register-based Research, Aarhus University, Aarhus, Denmark. 19. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. 20. Queensland Brain Institute, The University of Queensland, Brisbane, Australia. 21. Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Australia. 22. Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn. 23. Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine, University of Southern California, Los Angeles. 24. University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany. 25. Division of General Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria. 26. Early Intervention in Psychosis Advisory Unit for South-East Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 27. Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom. 28. Baker Heart and Diabetes Institute, Melbourne, Australia. 29. College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada. 30. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 31. Department of Psychiatry, Icahn School of Medicine, Mount Sinai Hospital, New York, New York. 32. Department of Genetics, University of North Carolina, Chapel Hill. 33. Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, University of London, London, United Kingdom. 34. Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London, London, United Kingdom. 35. Centro de Investigacion Biomedica en Red de Salud Mental, Spanish Network for Research in Mental Health, Sevilla, Spain. 36. Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Departamento de Psiquiatria, Universidad de Sevilla, Sevilla, Spain. 37. Treatment and Early Intervention in Psychosis Program, Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. 38. Division of Psychiatry, Imperial College London, London, United Kingdom. 39. Department of Biomedical and Neuro-motor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy. 40. Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team, Alma Mater Studiorum, University of Bologna, Bologna, Italy. 41. Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland. 42. Department of Medical Education, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom. 43. Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland. 44. School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. 45. Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. 46. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland. 47. 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. 48. Social Genetics and Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom. 49. South London and Maudsley National Health Service Mental Health Foundation Trust, London, United Kingdom. 50. Department of Social and Welfare Studies, Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden. 51. Centre For Public Health, Institute Of Clinical Sciences, Queens University Belfast, Belfast, United Kingdom. 52. UCL Queen Square Institute of Neurology, University College London, London, United Kingdom. 53. Faculty of Social Sciences, Department of Psychology, Beykoz University, Istanbul, Turkey. 54. 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. 55. Department of Applied Neuroscience and Neuroimaging, National Institute of Mental Health, Klecany, Czechia. 56. Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czechia. 57. Groupe Hospitalier Universitaire Psychiatrie Neurosciences Paris, Pôle Psychiatrie Précarité, Paris, France. 58. Department of Psychiatry, Istanbul University, Istanbul, Turkey. 59. Department of Psychiatry, University Hospital Marques de Valdecilla-Instituto de Investigación Marques de Valdecilla, Santander, Spain. 60. Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander, Spain. 61. Centro de Investigacion Biomedica en Red de Salud Mental, Spanish Network for Research in Mental Health, Santander, Spain.
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 (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.
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.
Authors: Roseann E Peterson; Alexis C Edwards; Silviu-Alin Bacanu; Danielle M Dick; Kenneth S Kendler; Bradley T Webb Journal: Am J Addict Date: 2017-07-17
Authors: Christopher C Chang; Carson C Chow; Laurent Cam Tellier; Shashaank Vattikuti; Shaun M Purcell; James J Lee Journal: Gigascience Date: 2015-02-25 Impact factor: 6.524
Authors: Giorgio Pistis; Javier Vázquez-Bourgon; Margot Fournier; Raoul Jenni; Martine Cleusix; Sergi Papiol; Sophie E Smart; Antonio F Pardiñas; James T R Walters; James H MacCabe; Zoltán Kutalik; Philippe Conus; Benedicto Crespo-Facorro; Kim Q Do Journal: Mol Psychiatry Date: 2022-09-21 Impact factor: 13.437