Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

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dc.authoridTiihonen, Jari/0000-0002-0400-6798
dc.authoridPardinas, Antonio/0000-0001-6845-7590
dc.authoridripke, stephan/0000-0003-3622-835X
dc.authoridSimons, Claudia/0000-0002-7637-3589
dc.authoridOkhuijsen-Pfeifer, Cynthia/0000-0002-9649-3879
dc.authoridEverall, Ian/0000-0003-3957-3861
dc.authoridGutwinski, Stefan/0009-0001-7150-6071
dc.contributor.authorOkhuijsen-Pfeifer, C.
dc.contributor.authorvan der Horst, M. Z.
dc.contributor.authorBousman, C. A.
dc.contributor.authorLin, B.
dc.contributor.authorvan Eijk, K. R.
dc.contributor.authorRipke, S.
dc.contributor.authorAyhan, Y.
dc.date.accessioned2025-01-21T16:41:20Z
dc.date.available2025-01-21T16:41:20Z
dc.date.issued2022
dc.departmentKırıkkale Üniversitesi
dc.description.abstractClozapine 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 x 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 = 6.84x10(-4)) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44x10(-3)). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78x10(-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.
dc.description.sponsorshipAlberta Innovates Strategic Research Project [G2018000868]; Springboard award by the Academy of Medical Sciences [SBF005 \1083]; Rudolf Magnus Young Talent Fellowship program of the University Medical Center Utrecht
dc.description.sponsorshipWe would like to thank R.L. Cummins, R. Kahn, M.K. Bakker, E. Bekema, H. Gijsman, A. Jongkind and P. Kleymann for their valuable input (see Supplementary Acknowledgements for details). Dr. Bousman reports a grant from Alberta Innovates Strategic Research Project G2018000868, during the conduct of the study. Dr. Pardinas' work is supported by a Springboard award by the Academy of Medical Sciences (SBF005 \1083). Dr Luykx' work is supported by a personal grant from the Rudolf Magnus Young Talent Fellowship program of the University Medical Center Utrecht.
dc.identifier.doi10.1038/s41398-022-01884-3
dc.identifier.issn2158-3188
dc.identifier.issue1
dc.identifier.pmid35393395
dc.identifier.scopus2-s2.0-85130836558
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1038/s41398-022-01884-3
dc.identifier.urihttps://hdl.handle.net/20.500.12587/24869
dc.identifier.volume12
dc.identifier.wosWOS:000779361900003
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherSpringernature
dc.relation.ispartofTranslational Psychiatry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20241229
dc.titleGenome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
dc.typeArticle

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