Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients—a genome-wide association study adjusting for smoking habits

Smith, Robert L.; O’Connell, Kevin; Athanasiu, Lavinia; Djurovic, Srdjan; Kringen, Marianne Kristiansen; Andreassen, Ole A.; Molden, Espen

doi:10.1038/s41398-020-00888-1

Cited by 38 publications

(54 citation statements)

References 38 publications

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“…Details of these SNPs can be seen in Table 1 . Another SNP reported to be associated with clozapine concentration (rs28379954; Smith et al, 2020 ) was also considered for analysis, but was not included due to poor imputation quality in CLOZUK2, which led to missing data in 78/208 individuals in our sample.…”

Section: Methodsmentioning

confidence: 99%

Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia

et al. 2021

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Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

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Section: Methodsmentioning

confidence: 99%

Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia

et al. 2021

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“…Several GWASs have identified candidate loci for clozapine blood concentrations and severe adverse drug reactions associated with clozapine, but limited focus has been given to symptomatic outcomes in patients using clozapine. [15][16][17][18][19] To our knowledge, there has only been one study that used a genome-wide approach to examine clozapine treatment outcome. 20 In that study of 123 clozapine-treated individuals, no statistically significant differences in schizophrenia-PRS between responders and non-responders were detected (N=123, p=0.06).…”

Section: Introductionmentioning

confidence: 99%

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

Okhuijsen-Pfeifer

Horst

Bousman

et al. 2021

Preprint

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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=1.03x10-3; 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.

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“…Evidence is already emerging that polymorphisms in genes encoding CYP enzymes are associated with clinically significant outcomes 49 . Interestingly, the drug concentrations and adverse drug reactions seem to be under strong monogenic or oligogenic control with only one or few loci associated with them (at least with current sample sizes) whereas many psychiatric disorders are extremely polygenic 50,51,52,53 . As accurate inference of metabolic activity of CYP2D6 cannot currently be done from GWAS chip data alone, the copy-number imputation method creates new opportunities for development towards and research of individualized medicine.…”

Section: Discussionmentioning

confidence: 99%

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Häkkinen

Kiiski

Lähteenvuo

et al. 2020

Preprint

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PurposeWe constructed a CYP2D6 copy-number imputation panel by combining copy-number information to GWAS chip data. In addition, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland.MethodsWe combined GWAS chip and CYP2D6 copy-number variation (CNV) data from the Breast Cancer Pain Genetics study (BrePainGen) to construct an imputation panel (N=902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9,262 non-related individuals passing genotype data quality control procedures. The panel performance was evaluated by genotyping the CNV from a subset (N=297) of SUPER-Finland participants.ResultsCYP2D6 CNV was imputed correctly in 272 (92%) individuals. Sensitivity and specificity for detecting a duplication were 0.986 and 0.946, respectively. Sensitivity and specificity for detecting a deletion using imputation were 0.886 and 0.966, respectively. Based on imputation, the frequency of a CYP2D6 duplication and deletion in the whole SUPER-Finland sample with 9,262 non-related individuals passing quality control were 8.5% and 2.7%, respectively. We confirm the higher frequency of CYP2D6 ultrarapid metabolizers in Finland compared with non-Finnish Europeans. Additionally, we confirm a 21-fold enrichment of the UGT1A1 decreased function variant rs4148323 (also known as 211G>A, G71R or UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland.ConclusionOur results demonstrate that imputation of CYP2D6 CNV is possible. The methodology is not accurate enough to be used in clinical decision making, but it enables studying CYP2D6 in large biobanks with genome-wide data. In addition, it allows for researchers to recontact patients with certain pharmacogenetic variations through biobanks. We show that bottle-necked populations may have pharmacogenetically important variants with allele frequencies very different from the main ancestral group. Future studies should assess whether these differences are large enough to cause clinically significant changes in trial results across different ancestral groups.

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Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients—a genome-wide association study adjusting for smoking habits

Cited by 38 publications

References 38 publications

Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia

Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia

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

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

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