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

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.

Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review

“…CYP1A2 and CYP2C19 activity scores were elevated and reduced in patients with clozapine resistance, respectively [ 100 ]. In addition, the CYP1A2*1F AA and AC genotypes [ 98 ], as well as the CYP2C19 *1/*17 genotype and *2 allele carriers [ 27 ] were at increased risk of developing clozapine resistance.…”

Associations Between Polygenic Risk Score Loading, Psychosis Liability, and Clozapine Use Among Individuals With Schizophrenia

“…Participants from the longitudinal Genetic Risk and Outcome in Psychosis (GROUP) cohort were in 1 of the following 5 groups: individuals with SSD taking clozapine (n = 186, defined as clozapine use at ≥1 of the 3 time points during follow-up; with additional participants from the cross-sectional Clozapine International Consortium [CLOZIN] cohort, n = 687), individuals with SSD for whom only antipsychotics other than clozapine had been recorded at 3 time points during the 6-year follow-up (n = 524), their siblings (n = 731) and parents (n = 695), and unrelated healthy controls (n = 369). GROUP and CLOZIN (3192 participants in total) are observational cohorts conceived to elucidate genetic determinants of SSD (eMethods in Supplement 1).…”

“…Genotyping, genotype- and participant-level quality control, genotype imputation, PRS procedures, and computation of explained variances are based on previously described methods (eMethods, eTables 1 and 2, and eFigure 1 in Supplement 1). Polygenic risk scores for SCZ were derived from a European-ancestry study and generated by applying a bayesian framework method that uses continuous shrinkage (cs) on SNP effect sizes. PRS-cs-auto is robust to varying genetic architectures, provides substantial computational advantages, and enables multivariate modeling of local linkage disequilibrium patterns (eTable 3 and eMethods in Supplement 1).…”

Polygenetic risk scores and phenotypic constellations of obsessive–compulsive disorder in clozapine-treated schizophrenia

“…The study population was recruited as a part of the larger multicenter Clozapine International Consortium (CLO-ZIN), which is led by the University Medical Center Utrecht. This study aimed to investigate the underlying genetic architecture of treatment-resistant SCZ and identify clinical and genetic predictors of CLZ effectiveness and the occurrence of side effects [35] (5) ability to provide informed consent. Exclusion criteria were: (1) admission to a psychiatric unit involuntarily in the context of an 'inbewaringstelling' (IBS), a particular compulsory treatment included in Dutch law, and (2) a history of Parkinson's disease.…”

“…umich. edu), followed by post-imputation removal of all SNPs with a minor allele frequency (MAF) < 0.05 or an imputation score (R 2 ) < 0.3 [35].…”