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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., van Amelsvoort, T., Bartels-Velthuis, A. A., Bruggeman, R., Cahn, W., Guloksuz, S., de Haan, L., Kahn, R. S., Schirmbeck, F., Simons, C. J. P., van Os, J., Alizadeh, B. Z., Luykx, J. J., Rutten, B. P. F., van Winkel, R., 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. ORCID:, 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. ORCID:, Yağcıoğlu, A. E. Anil, Tiihonen, J., Hasan, A. and Luykx, J. J. 2022. Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders. Translational Psychiatry 12 , 145. 10.1038/s41398-022-01884-3

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Springer Nature [academic journals on]
ISSN: 2158-3188
Date of First Compliant Deposit: 8 June 2022
Date of Acceptance: 7 March 2022
Last Modified: 12 May 2023 21:13

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