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Multicenter Study
. 2022 Apr 7;12(1):145.
doi: 10.1038/s41398-022-01884-3.

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

C Okhuijsen-Pfeifer #  1   2 , M Z van der Horst #  1   2   3 , C A Bousman #  4   5   6   7 , B Lin #  1   2 , K R van Eijk  2 , S Ripke  8 , Y Ayhan  9 , M O Babaoglu  10 , M Bak  11   12 , W Alink  13 , H van Beek  14 , E Beld  15 , A Bouhuis  16 , M Edlinger  17 , I M Erdogan  9 , A Ertuğrul  9 , G Yoca  9   18 , I P Everall  7   19 , T Görlitz  20   21 ; GROUP (Genetic Risk and Outcome of Psychosis) investigators; K P Grootens  22   23 , S Gutwinski  8 , T Hallikainen  24 , E Jeger-Land  25 , M de Koning  25   26 , M Lähteenvuo  24 , S E Legge  27 , S Leucht  28 , C Morgenroth  8 , A Müderrisoğlu  29 , A Narang  4 , C Pantelis  7 , A F Pardiñas  27 , T Oviedo-Salcedo  20 , J Schneider-Thoma  28 , S Schreiter  8   30 , E Repo-Tiihonen  24 , H Tuppurainen  24 , M Veereschild  3 , S Veerman  31 , M de Vos  3 , E Wagner  20 , D Cohen  32 , J P A M Bogers  33 , J T R Walters  27 , A E Anil Yağcıoğlu  9 , J Tiihonen  24   34   35 , A Hasan  20   21 , J J Luykx  36   37   38
Collaborators, Affiliations
Multicenter Study

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

C Okhuijsen-Pfeifer et al. Transl Psychiatry. .

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.

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Conflict of interest statement

Dr. Bousman reports he has received in-kind testing kits from Myriad Neuroscience, CNSDose, Genomind, and AB-Biotics for research purposes but has not received payments or received any equity, stocks, or options in these companies or any other pharmacogenetic companies. Dr. Lähteenvuo reports being a shareholder and board member at Genomi Solutions Ltd and Nursie Health Ltd; receiving research grants or awards from the Finnish Medical Foundation and Emil Aaltonen Foundation; receiving travel grants or speakers’ honoraria from Sunovion Ltd, Janssen-Cilag, Otsuka Pharmaceutical Ltd, Lundbeck Ltd, Orion Pharma ltd; and working as a coordinator for a research project funded by the Stanley Foundation. Dr. A.E. Anil Yağcıoğlu has recently received travel grants or speakers’ honoraria from Janssen, Otsuka; is a member of the advisory board for Janssen, Otsuka; is currently participating in an international clinical trial funded by Janssen. Dr. Tiihonen reports personal fees from the Finnish Medicines Agency (Fimea), European Medicines Agency (EMA), Eli Lilly, Janssen, Lundbeck, and Otsuka; is a member of the advisory board for Lundbeck; and has participated in research projects funded by grants from Eli Lilly and Janssen to his employing institution. All other authors have declared that there are no conflicts of interest in relation to the subject of this study.

Figures

Fig. 1
Fig. 1. Genome-wide association analysis of symptom severity while on clozapine.
A, B Manhattan plots depicting the genome-wide association results of symptom severity while on clozapine for quantitative and binary outcome. The X-axis shows the chromosomal positions. The Y-axis shows –log10 (p values). The red line illustrates the genome-wide significance level of p = 5 × 10−8, and the blue line illustrates the suggestive level of significance of p = 5 × 10−5. The arrows indicate the top loci and the closest genes.
Fig. 2
Fig. 2. Association between symptom severity while on clozapine and polygenic risk scores for schizophrenia.
A, B. Bar plot illustrating the explained variance for the association of schizophrenia-PRS with binary outcome at several pt, adjusted for sex, age, and 10 PCs. pt are displayed on the X-axis, where the number of included SNPs increases with more lenient pt. Δ Explained variance represents the Nagelkerke R2 (shown as %). The red dots represent the significance of the association results (-Log 10 p value). The dashed line represents a nominal significance-level of p < 0.05 (A). Individual risk prediction: higher schizophrenia-PRS was associated with higher positive predictive value for low symptom severity. Whiskers represent confidence intervals (±1.96 × standard error) around the central positive predictive value estimate (B).
Fig. 3
Fig. 3. Violin plots displaying the distribution in symptom severity while on clozapine by polygenic risk score subgroups.
A, B Violin plots of schizophrenia-PRS (PRS-SCZ) comparison for binary outcome, and cross-disorder-PRS (PRS-CDG) tertile comparison for quantitative outcome. For both analyses the best fitting p was used. The dashed line illustrates the mean PRS-SCZ (A) and the mean residual CGI-S score (B) in all participants. Differences were determined by linear regression of quantitative outcome on PRS tertile and using a T-test for binary outcome, corrected for sex, age, and 10 PCs (Supplementary Methods). **p < 5.0 × 10−3. ns nonsignificant.
Fig. 4
Fig. 4. Association between CYP-activity scores, symptom severity while on clozapine and dose-adjusted clozapine levels.
A–I. Association of corrected CYP2C19, CYP1A2, and CYP2D6 genotype-predicted activity scores with symptom severity while on clozapine and dose-adjusted clozapine levels.
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