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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. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Smart, Sophie E. (författare)
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
Willcocks, Isabella R. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
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Holmans, Peter A. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Dennison, Charlotte A. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Lynham, Amy J. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Legge, Sophie E. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Baune, Bernhard T. (författare)
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,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
Bigdeli, Tim B. (författare)
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
Cairns, Murray J. (författare)
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
Corvin, Aiden (författare)
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
Fanous, Ayman H. (författare)
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
Frank, Josef (författare)
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany
Kelly, Brian (författare)
School of Medicine & Public Health, The University of Newcastle, Newcastle, Australia
McQuillin, Andrew (författare)
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom
Melle, Ingrid (författare)
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
Mortensen, Preben B. (författare)
National Centre for Register-based Research, Aarhus University, Aarhus, Denmark;The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
Mowry, Bryan J. (författare)
Queensland Brain Institute, The University of Queensland, Brisbane, Australia;Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Australia
Pato, Carlos N. (författare)
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
Periyasamy, Sathish (författare)
Queensland Brain Institute, The University of Queensland, Brisbane, Australia;Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Australia
Rietschel, Marcella (författare)
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany
Rujescu, Dan (författare)
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
Simonsen, Carmen (författare)
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
St Clair, David (författare)
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
Tooney, Paul (författare)
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia;Hunter Medical Research Institute, Newcastle, Australia
Wu, Jing Qin (författare)
Baker Heart and Diabetes Institute, Melbourne, Australia
Andreassen, Ole A. (författare)
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
Kowalec, Kaarina (författare)
Karolinska Institutet,College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada;Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Sullivan, Patrick F. (författare)
Karolinska Institutet,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
Murray, Robin M. (författare)
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
Owen, Michael J. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
MacCabe, James H. (författare)
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
O’Donovan, Michael C. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Walter, James, T. (författare)
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
Homman, Lina (författare)
Linköpings universitet,Avdelningen för åldrande och social förändring,Avdelningen för funktionsnedsättning och samhälle,Filosofiska fakulteten,Centre For Public Health, Institute Of Clinical Sciences, Queens University Belfast, Belfast, United Kingdom,The Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium
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 (creator_code:org_t)
Chicago, IL, United States : American Medical Association, 2022
2022
Engelska.
Ingår i: JAMA psychiatry. - Chicago, IL, United States : American Medical Association. - 2168-6238 .- 2168-622X. ; 79:3, s. 260-269
Relaterad länk:
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https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

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