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

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, K P GrootensS 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*, GROUP (Genetic Risk and Outcome of Psychosis) investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Web of Science)


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.

Original languageEnglish
Article number145
Number of pages9
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 7 Apr 2022


  • Antipsychotic Agents/therapeutic use
  • Clozapine/therapeutic use
  • Cytochrome P-450 CYP1A2/genetics
  • Cytochrome P-450 CYP2C19/genetics
  • Cytochrome P-450 CYP2D6/genetics
  • Genome-Wide Association Study
  • Humans
  • Schizophrenia/chemically induced
  • CYP2C19

Cite this