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Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
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...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
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Nature Publishing Group UK
2022
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989876/ https://www.ncbi.nlm.nih.gov/pubmed/35393395 http://dx.doi.org/10.1038/s41398-022-01884-3 |
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| author | Okhuijsen-Pfeifer, C. van der Horst, M. Z. Bousman, C. A. Lin, B. van Eijk, K. R. Ripke, S. Ayhan, Y. Babaoglu, M. O. Bak, M. Alink, W. van Beek, H. Beld, E. Bouhuis, A. Edlinger, M. Erdogan, I. M. Ertuğrul, A. Yoca, G. Everall, I. P. Görlitz, T. Grootens, K. P. Gutwinski, S. Hallikainen, T. Jeger-Land, E. de Koning, M. Lähteenvuo, M. Legge, S. E. Leucht, S. Morgenroth, C. Müderrisoğlu, A. Narang, A. Pantelis, C. Pardiñas, A. F. Oviedo-Salcedo, T. Schneider-Thoma, J. Schreiter, S. Repo-Tiihonen, E. Tuppurainen, H. Veereschild, M. Veerman, S. de Vos, M. Wagner, E. Cohen, D. Bogers, J. P. A. M. Walters, J. T. R. Yağcıoğlu, A. E. Anil Tiihonen, J. Hasan, A. Luykx, J. J. |
| author_facet | Okhuijsen-Pfeifer, C. van der Horst, M. Z. Bousman, C. A. Lin, B. van Eijk, K. R. Ripke, S. Ayhan, Y. Babaoglu, M. O. Bak, M. Alink, W. van Beek, H. Beld, E. Bouhuis, A. Edlinger, M. Erdogan, I. M. Ertuğrul, A. Yoca, G. Everall, I. P. Görlitz, T. Grootens, K. P. Gutwinski, S. Hallikainen, T. Jeger-Land, E. de Koning, M. Lähteenvuo, M. Legge, S. E. Leucht, S. Morgenroth, C. Müderrisoğlu, A. Narang, A. Pantelis, C. Pardiñas, A. F. Oviedo-Salcedo, T. Schneider-Thoma, J. Schreiter, S. Repo-Tiihonen, E. Tuppurainen, H. Veereschild, M. Veerman, S. de Vos, M. Wagner, E. Cohen, D. Bogers, J. P. A. M. Walters, J. T. R. Yağcıoğlu, A. E. Anil Tiihonen, J. Hasan, A. Luykx, J. J. |
| author_sort | Okhuijsen-Pfeifer, C. |
| collection | PubMed |
| description | 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. |
| format | Online Article Text |
| id | pubmed-8989876 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2022 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-89898762022-04-22 Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders Okhuijsen-Pfeifer, C. van der Horst, M. Z. Bousman, C. A. Lin, B. van Eijk, K. R. Ripke, S. Ayhan, Y. Babaoglu, M. O. Bak, M. Alink, W. van Beek, H. Beld, E. Bouhuis, A. Edlinger, M. Erdogan, I. M. Ertuğrul, A. Yoca, G. Everall, I. P. Görlitz, T. Grootens, K. P. Gutwinski, S. Hallikainen, T. Jeger-Land, E. de Koning, M. Lähteenvuo, M. Legge, S. E. Leucht, S. Morgenroth, C. Müderrisoğlu, A. Narang, A. Pantelis, C. Pardiñas, A. F. Oviedo-Salcedo, T. Schneider-Thoma, J. Schreiter, S. Repo-Tiihonen, E. Tuppurainen, H. Veereschild, M. Veerman, S. de Vos, M. Wagner, E. Cohen, D. Bogers, J. P. A. M. Walters, J. T. R. Yağcıoğlu, A. E. Anil Tiihonen, J. Hasan, A. Luykx, J. J. Transl Psychiatry Article 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. Nature Publishing Group UK 2022-04-07 /pmc/articles/PMC8989876/ /pubmed/35393395 http://dx.doi.org/10.1038/s41398-022-01884-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
| spellingShingle | Article Okhuijsen-Pfeifer, C. van der Horst, M. Z. Bousman, C. A. Lin, B. van Eijk, K. R. Ripke, S. Ayhan, Y. Babaoglu, M. O. Bak, M. Alink, W. van Beek, H. Beld, E. Bouhuis, A. Edlinger, M. Erdogan, I. M. Ertuğrul, A. Yoca, G. Everall, I. P. Görlitz, T. Grootens, K. P. Gutwinski, S. Hallikainen, T. Jeger-Land, E. de Koning, M. Lähteenvuo, M. Legge, S. E. Leucht, S. Morgenroth, C. Müderrisoğlu, A. Narang, A. Pantelis, C. Pardiñas, A. F. Oviedo-Salcedo, T. Schneider-Thoma, J. Schreiter, S. Repo-Tiihonen, E. Tuppurainen, H. Veereschild, M. Veerman, S. de Vos, M. Wagner, E. Cohen, D. Bogers, J. P. A. M. Walters, J. T. R. Yağcıoğlu, A. E. Anil Tiihonen, J. Hasan, A. Luykx, J. J. Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders |
| 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 |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989876/ https://www.ncbi.nlm.nih.gov/pubmed/35393395 http://dx.doi.org/10.1038/s41398-022-01884-3 |
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