Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
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 var...
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Nature Publishing Group
2022-04-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-022-01884-3 |
| _version_ | 1811290438430097408 |
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| author | 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 |
| author_facet | 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 |
| author_sort | C. Okhuijsen-Pfeifer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T04:12:55Z |
| format | Article |
| id | doaj.art-336ada6c3f194f2c90127be5920de5e1 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-04-13T04:12:55Z |
| publishDate | 2022-04-01 |
| publisher | Nature Publishing Group |
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| series | Translational Psychiatry |
| spelling | doaj.art-336ada6c3f194f2c90127be5920de5e12022-12-22T03:03:03ZengNature Publishing GroupTranslational Psychiatry2158-31882022-04-011211910.1038/s41398-022-01884-3Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disordersC. Okhuijsen-Pfeifer0M. Z. van der Horst1C. A. Bousman2B. Lin3K. R. van Eijk4S. Ripke5Y. Ayhan6M. O. Babaoglu7M. Bak8W. Alink9H. van Beek10E. Beld11A. Bouhuis12M. Edlinger13I. M. Erdogan14A. Ertuğrul15G. Yoca16I. P. Everall17T. Görlitz18GROUP (Genetic Risk and Outcome of Psychosis) investigatorsK. P. Grootens19S. Gutwinski20T. Hallikainen21E. Jeger-Land22M. de Koning23M. Lähteenvuo24S. E. Legge25S. Leucht26C. Morgenroth27A. Müderrisoğlu28A. Narang29C. Pantelis30A. F. Pardiñas31T. Oviedo-Salcedo32J. Schneider-Thoma33S. Schreiter34E. Repo-Tiihonen35H. Tuppurainen36M. Veereschild37S. Veerman38M. de Vos39E. Wagner40D. Cohen41J. P. A. M. Bogers42J. T. R. Walters43A. E. Anil Yağcıoğlu44J. Tiihonen45A. Hasan46J. J. Luykx47Department of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain CenterDepartment of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain CenterDepartment of Medical Genetics, University of CalgaryDepartment of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain CenterDepartment of Translational Neuroscience, University Medical Center Utrecht, Utrecht University, Brain CenterCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and PsychotherapyDepartment of Psychiatry, Faculty of Medicine, Hacettepe UniversityDepartment of Pharmacology, Faculty of Medicine, Hacettepe UniversityDepartment of Psychiatry and Neuropsychology, Maastricht UniversityMulticomplexe Zorg, Pro PersonaClinical Recovery Clinic, Mental Health Services RivierduinenMental Health Organization North‐Holland North location Den HelderProgram for early psychosis & severe mental illness, Pro Persona Mental HealthcareDepartment of Psychiatry, Psychotherapy and Psychosomatics, Division for Psychiatry I, Medical University InnsbruckDepartment of Psychiatry, Faculty of Medicine, Hacettepe UniversityDepartment of Psychiatry, Faculty of Medicine, Hacettepe UniversityDepartment of Psychiatry, Faculty of Medicine, Hacettepe UniversityDepartment of Psychiatry, University of Melbourne, Melbourne Neuropsychiatry CentreDepartment of Psychiatry and Psychotherapy, University Hospital, LMU MunichReinier van ArkelCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and PsychotherapyDepartment of Forensic Psychiatry, University of Kuopio, Niuvanniemi HospitalArkin, Institute for Mental HealthArkin, Institute for Mental HealthDepartment of Forensic Psychiatry, University of Kuopio, Niuvanniemi HospitalDivision of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff UniversityDepartment of Psychiatry and Psychotherapy, School of Medicine, Klinikum rechts der Isar, Technical University of MunichCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and PsychotherapyDepartment of Pharmacology, Faculty of Medicine, Kırıkkale UniversityDepartment of Medical Genetics, University of CalgaryDepartment of Psychiatry, University of Melbourne, Melbourne Neuropsychiatry CentreDivision of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff UniversityDepartment of Psychiatry and Psychotherapy, University Hospital, LMU MunichDepartment of Psychiatry and Psychotherapy, School of Medicine, Klinikum rechts der Isar, Technical University of MunichCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and PsychotherapyDepartment of Forensic Psychiatry, University of Kuopio, Niuvanniemi HospitalDepartment of Forensic Psychiatry, University of Kuopio, Niuvanniemi HospitalGGNet Mental HealthMental Health Organization North‐Holland North location AlkmaarGGNet Mental HealthDepartment of Psychiatry and Psychotherapy, University Hospital, LMU MunichMental Health Organization North‐Holland North location HeerhugowaardHigh Care Clinics, Mental Health Services RivierduinenDivision of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff UniversityDepartment of Psychiatry, Faculty of Medicine, Hacettepe UniversityDepartment of Forensic Psychiatry, University of Kuopio, Niuvanniemi HospitalDepartment of Psychiatry and Psychotherapy, University Hospital, LMU MunichDepartment of Psychiatry, University Medical Center Utrecht, Utrecht University, Brain CenterAbstract 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.https://doi.org/10.1038/s41398-022-01884-3 |
| spellingShingle | 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 Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders Translational Psychiatry |
| title | Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders |
| title_full | Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders |
| title_fullStr | Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders |
| title_full_unstemmed | Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders |
| title_short | Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders |
| title_sort | genome wide association analyses of symptom severity among clozapine treated patients with schizophrenia spectrum disorders |
| url | https://doi.org/10.1038/s41398-022-01884-3 |
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