Translational Psychiatry (Apr 2022)
Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
- C. Okhuijsen-Pfeifer,
- M. Z. van der Horst,
- C. A. Bousman,
- B. Lin,
- K. R. van Eijk,
- S. Ripke,
- Y. Ayhan,
- M. O. Babaoglu,
- M. Bak,
- W. Alink,
- H. van Beek,
- E. Beld,
- A. Bouhuis,
- M. Edlinger,
- I. M. Erdogan,
- A. Ertuğrul,
- G. Yoca,
- I. P. Everall,
- T. Görlitz,
- GROUP (Genetic Risk and Outcome of Psychosis) investigators,
- K. P. Grootens,
- S. Gutwinski,
- T. Hallikainen,
- E. Jeger-Land,
- M. de Koning,
- M. Lähteenvuo,
- S. E. Legge,
- S. Leucht,
- C. Morgenroth,
- A. Müderrisoğlu,
- A. Narang,
- C. Pantelis,
- A. F. Pardiñas,
- T. Oviedo-Salcedo,
- J. Schneider-Thoma,
- S. Schreiter,
- E. Repo-Tiihonen,
- H. Tuppurainen,
- M. Veereschild,
- S. Veerman,
- M. de Vos,
- E. Wagner,
- D. Cohen,
- J. P. A. M. Bogers,
- J. T. R. Walters,
- A. E. Anil Yağcıoğlu,
- J. Tiihonen,
- A. Hasan,
- J. J. Luykx
Affiliations
- C. Okhuijsen-Pfeifer
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain Center
- M. Z. van der Horst
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain Center
- C. A. Bousman
- Department of Medical Genetics, University of Calgary
- B. Lin
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain Center
- K. R. van Eijk
- Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Brain Center
- S. Ripke
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and Psychotherapy
- Y. Ayhan
- Department of Psychiatry, Faculty of Medicine, Hacettepe University
- M. O. Babaoglu
- Department of Pharmacology, Faculty of Medicine, Hacettepe University
- M. Bak
- Department of Psychiatry and Neuropsychology, Maastricht University
- W. Alink
- Multicomplexe Zorg, Pro Persona
- H. van Beek
- Clinical Recovery Clinic, Mental Health Services Rivierduinen
- E. Beld
- Mental Health Organization North‐Holland North location Den Helder
- A. Bouhuis
- Program for early psychosis & severe mental illness, Pro Persona Mental Healthcare
- M. Edlinger
- Department of Psychiatry, Psychotherapy and Psychosomatics, Division for Psychiatry I, Medical University Innsbruck
- I. M. Erdogan
- Department of Psychiatry, Faculty of Medicine, Hacettepe University
- A. Ertuğrul
- Department of Psychiatry, Faculty of Medicine, Hacettepe University
- G. Yoca
- Department of Psychiatry, Faculty of Medicine, Hacettepe University
- I. P. Everall
- Department of Psychiatry, University of Melbourne, Melbourne Neuropsychiatry Centre
- T. Görlitz
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich
- GROUP (Genetic Risk and Outcome of Psychosis) investigators
- K. P. Grootens
- Reinier van Arkel
- S. Gutwinski
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and Psychotherapy
- T. Hallikainen
- Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital
- E. Jeger-Land
- Arkin, Institute for Mental Health
- M. de Koning
- Arkin, Institute for Mental Health
- M. Lähteenvuo
- Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital
- S. E. Legge
- Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University
- S. Leucht
- Department of Psychiatry and Psychotherapy, School of Medicine, Klinikum rechts der Isar, Technical University of Munich
- C. Morgenroth
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and Psychotherapy
- A. Müderrisoğlu
- Department of Pharmacology, Faculty of Medicine, Kırıkkale University
- A. Narang
- Department of Medical Genetics, University of Calgary
- C. Pantelis
- Department of Psychiatry, University of Melbourne, Melbourne Neuropsychiatry Centre
- A. F. Pardiñas
- Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University
- T. Oviedo-Salcedo
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich
- J. Schneider-Thoma
- Department of Psychiatry and Psychotherapy, School of Medicine, Klinikum rechts der Isar, Technical University of Munich
- S. Schreiter
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and Psychotherapy
- E. Repo-Tiihonen
- Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital
- H. Tuppurainen
- Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital
- M. Veereschild
- GGNet Mental Health
- S. Veerman
- Mental Health Organization North‐Holland North location Alkmaar
- M. de Vos
- GGNet Mental Health
- E. Wagner
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich
- D. Cohen
- Mental Health Organization North‐Holland North location Heerhugowaard
- J. P. A. M. Bogers
- High Care Clinics, Mental Health Services Rivierduinen
- J. T. R. Walters
- Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University
- A. E. Anil Yağcıoğlu
- Department of Psychiatry, Faculty of Medicine, Hacettepe University
- J. Tiihonen
- Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital
- A. Hasan
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich
- J. J. Luykx
- Department of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain Center
- DOI
- https://doi.org/10.1038/s41398-022-01884-3
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 9
Abstract
Abstract Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.
