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INTRODUCTION: Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment. METHODS: Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups. RESULTS: Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005). CONCLUSION: LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.
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Antipsicóticos , Clozapina , Monitoreo de Drogas , Humanos , Antipsicóticos/administración & dosificación , Clozapina/administración & dosificación , Femenino , Masculino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Monitoreo de Drogas/métodos , Noruega , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/sangre , Esquizofrenia Resistente al Tratamiento/tratamiento farmacológico , Fumarato de Quetiapina/administración & dosificaciónRESUMEN
Cytochrome P450 2D6 (CYP2D6) is important for metabolism of 20%-25% of all clinically used drugs. Many known genetic variants contribute to the large interindividual variability in CYP2D6 metabolism, but much is still unexplained. We recently described that nuclear factor 1B (NFIB) regulates hepatic CYP2D6 expression with the minor allele of NFIB rs28379954 T>C significantly increasing CYP2D6-mediated risperidone metabolism. In this study, we investigated the effect of NFIB T>C on metabolism of solanidine, a dietary CYP2D6 substrate. Analyses of solanidine and metabolites (M414, M416, and M444) were performed by ultra-high performance liquid chromatography-high-resolution mass spectrometry in a cohort of 463 CYP2D6-genotyped patients of which with 58 (12.5%) carried NFIB TC (n = 56) or CC (n = 2). Increased metabolism of solanidine was found in CYP2D6 normal metabolizers (NMs; n = 258, 55.7%) carrying the NFIB C variant (n = 27, 5.8%) with 2.83- and 3.38-fold higher M416-to-solanidine (p = 0.039) and M444-to-solanidine (p = 0.046) ratios, respectively, whereas this effect was not significant among intermediate metabolizers (n = 166, 35.9%) (p ≥ 0.09). Importantly, no effect of the NFIB polymorphism on solanidine metabolism was seen in TC or CC carriers lacking CYP2D6 activity (poor metabolizers, n = 30, 6.5%, p ≥ 0.74). Furthermore, the NFIB polymorphism significantly explained variability in solanidine metabolism (M414 p = 0.013, M416 p = 0.020, and M416 and M444 p = 0.009) in multiple linear regression models for each metabolic ratio in the entire population, correcting for covariates (including CYP2D6 genotypes). Thus, the study confirms the effect of NFIB in regulating CYP2D6 activity, suggesting an about 200% increase in CYP2D6-mediated clearance in NMs being NFIB CT or CC carriers, comprising around 6% of Europeans.
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Citocromo P-450 CYP2D6 , Diosgenina , Humanos , Citocromo P-450 CYP2D6/genética , Alelos , Catálisis , Factores de Transcripción NFIRESUMEN
BACKGROUND: Opioid use disorder (OUD), a serious health burden worldwide, is associated with lower cognitive function. Recent studies have demonstrated a negative genetic correlation between OUD and general cognitive ability (COG), indicating a shared genetic basis. However, the specific genetic variants involved, and the underlying molecular mechanisms remain poorly understood. Here, we aimed to quantify and identify the genetic basis underlying OUD and COG. METHODS: We quantified the extent of genetic overlap between OUD and COG using a bivariate causal mixture model (MiXeR) and identified specific genetic loci applying conditional/conjunctional FDR. Finally, we investigated biological function and expression of implicated genes using available resources. RESULTS: We estimated that ~94% of OUD variants (4.8k out of 5.1k variants) also influence COG. We identified three novel OUD risk loci and one locus shared between OUD and COG. Loci identified implicated biological substrates in the basal ganglia. CONCLUSION: We provide new insights into the complex genetic risk architecture of OUD and its genetic relationship with COG.
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Estudio de Asociación del Genoma Completo , Trastornos Relacionados con Opioides , Humanos , Cognición , Trastornos Relacionados con Opioides/genéticaRESUMEN
Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.
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Cognición , Estudio de Asociación del Genoma Completo , Esquizofrenia , Humanos , Esquizofrenia/genética , Cognición/fisiología , Predisposición Genética a la Enfermedad , Herencia Multifactorial/genética , Femenino , Masculino , Polimorfismo de Nucleótido Simple , Genómica/métodos , Psicología del Esquizofrénico , Disfunción Cognitiva/genéticaRESUMEN
Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.
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Toxoplasma , Toxoplasmosis , Humanos , Femenino , Adulto , Masculino , Inflamasomas , Interleucina-18 , Inmunoglobulina GRESUMEN
Comorbidities are an increasing global health challenge. Accumulating evidence suggests overlapping genetic architectures underlying comorbid complex human traits and disorders. The bivariate causal mixture model (MiXeR) can quantify the polygenic overlap between complex phenotypes beyond global genetic correlation. Still, the pattern of genetic overlap between three distinct phenotypes, which is important to better characterize multimorbidities, has previously not been possible to quantify. Here, we present and validate the trivariate MiXeR tool, which disentangles the pattern of genetic overlap between three phenotypes using summary statistics from genome-wide association studies (GWAS). Our simulations show that the trivariate MiXeR can reliably reconstruct different patterns of genetic overlap. We further demonstrate how the tool can be used to estimate the proportions of genetic overlap between three phenotypes using real GWAS data, providing examples of complex patterns of genetic overlap between diverse human traits and diseases that could not be deduced from bivariate analyses. This contributes to a better understanding of the etiology of complex phenotypes and the nature of their relationship, which may aid in dissecting comorbidity patterns and their biological underpinnings.
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Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different aspects of genetic overlap between COG and epilepsies. We used the largest available genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes 'all epilepsy', focal epilepsies and genetic generalized epilepsies (GGE), and as well as specific subtypes. We functionally annotated the identified loci using a variety of biological resources and validated the results in independent samples. Results: Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than 'all epilepsy', GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k - 2.9k variants). The other epilepsy phenotypes were insufficiently powered for analysis. We show extensive genetic overlap between COG and epilepsies with significant negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and 'all epilepsy', and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), 'all epilepsy' (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 1.0 × 10-14; 'all epilepsy': p = 5.6 × 10-3). Significance: Our study demonstrates a substantial genetic basis shared between epilepsies and COG and identifies novel overlapping genomic loci. Enhancing our understanding of the relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.
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While genome-wide association studies are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. Here we developed the GSA-MiXeR analytical tool for gene set analysis (GSA), which fits a model for the heritability of individual genes, accounting for linkage disequilibrium across variants and allowing the quantification of partitioned heritability and fold enrichment for small gene sets. We validated the method using extensive simulations and sensitivity analyses. When applied to a diverse selection of complex traits and disorders, including schizophrenia, GSA-MiXeR prioritizes gene sets with greater biological specificity compared to standard GSA approaches, implicating voltage-gated calcium channel function and dopaminergic signaling for schizophrenia. Such biologically relevant gene sets, often with fewer than ten genes, are more likely to provide insights into the pathobiology of complex diseases and highlight potential drug targets.
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Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Esquizofrenia , Humanos , Estudio de Asociación del Genoma Completo/métodos , Esquizofrenia/genética , Herencia Multifactorial/genética , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Predisposición Genética a la Enfermedad , Mapeo Cromosómico/métodos , Simulación por Computador , Carácter Cuantitativo HeredableRESUMEN
Background and Objectives: Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated the extent to which these phenotypes share genetic influences. Methods: We analyzed genome-wide association study data on common epilepsies (n = 69,995) and TH and SA (n = 32,877) using Gaussian mixture modeling MiXeR and conjunctional false discovery rate (conjFDR) analysis to quantify their shared genetic architecture and identify overlapping loci. We biologically interrogated the loci using a variety of resources and validated in independent samples. Results: The epilepsies (2.4 k-2.9 k variants) were more polygenic than both SA (1.8 k variants) and TH (1.3 k variants). Despite absent genome-wide genetic correlations, there was a substantial genetic overlap between SA and genetic generalized epilepsy (GGE) (1.1 k), all epilepsies (1.1 k), and juvenile myoclonic epilepsy (JME) (0.7 k), as well as between TH and GGE (0.8 k), all epilepsies (0.7 k), and JME (0.8 k), estimated with MiXeR. Furthermore, conjFDR analysis identified 15 GGE loci jointly associated with SA and 15 with TH, 3 loci shared between SA and childhood absence epilepsy, and 6 loci overlapping between SA and JME. 23 loci were novel for epilepsies and 11 for cortical morphology. We observed a high degree of sign concordance in the independent samples. Discussion: Our findings show extensive genetic overlap between generalized epilepsies and cortical morphology, indicating a complex genetic relationship with mixed-effect directions. The results suggest that shared genetic influences may contribute to cortical abnormalities in epilepsies.
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Genomic prediction of antipsychotic dose and polypharmacy has been difficult, mainly due to limited access to large cohorts with genetic and drug prescription data. In this proof of principle study, we investigated if genetic liability for schizophrenia is associated with high dose requirements of antipsychotics and antipsychotic polypharmacy, using real-world registry and biobank data from five independent Nordic cohorts of a total of N = 21,572 individuals with psychotic disorders (schizophrenia, bipolar disorder, and other psychosis). Within regression models, a polygenic risk score (PRS) for schizophrenia was studied in relation to standardized antipsychotic dose as well as antipsychotic polypharmacy, defined based on longitudinal prescription registry data as well as health records and self-reported data. Meta-analyses across the five cohorts showed that PRS for schizophrenia was significantly positively associated with prescribed (standardized) antipsychotic dose (beta(SE) = 0.0435(0.009), p = 0.0006) and antipsychotic polypharmacy defined as taking ≥2 antipsychotics (OR = 1.10, CI = 1.05-1.21, p = 0.0073). The direction of effect was similar in all five independent cohorts. These findings indicate that genotypes may aid clinically relevant decisions on individual patients´ antipsychotic treatment. Further, the findings illustrate how real-world data have the potential to generate results needed for future precision medicine approaches in psychiatry.
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Antipsicóticos , Bancos de Muestras Biológicas , Herencia Multifactorial , Polifarmacia , Sistema de Registros , Esquizofrenia , Humanos , Antipsicóticos/administración & dosificación , Antipsicóticos/uso terapéutico , Masculino , Femenino , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Persona de Mediana Edad , Adulto , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/genética , Estudios de Cohortes , AncianoRESUMEN
Despite great progress on methods for case-control polygenic prediction (e.g. schizophrenia vs. control), there remains an unmet need for a method that genetically distinguishes clinically related disorders (e.g. schizophrenia (SCZ) vs. bipolar disorder (BIP) vs. depression (MDD) vs. control); such a method could have important clinical value, especially at disorder onset when differential diagnosis can be challenging. Here, we introduce a method, Differential Diagnosis-Polygenic Risk Score (DDx-PRS), that jointly estimates posterior probabilities of each possible diagnostic category (e.g. SCZ=50%, BIP=25%, MDD=15%, control=10%) by modeling variance/covariance structure across disorders, leveraging case-control polygenic risk scores (PRS) for each disorder (computed using existing methods) and prior clinical probabilities for each diagnostic category. DDx-PRS uses only summary-level training data and does not use tuning data, facilitating implementation in clinical settings. In simulations, DDx-PRS was well-calibrated (whereas a simpler approach that analyzes each disorder marginally was poorly calibrated), and effective in distinguishing each diagnostic category vs. the rest. We then applied DDx-PRS to Psychiatric Genomics Consortium SCZ/BIP/MDD/control data, including summary-level training data from 3 case-control GWAS ( N =41,917-173,140 cases; total N =1,048,683) and held-out test data from different cohorts with equal numbers of each diagnostic category (total N =11,460). DDx-PRS was well-calibrated and well-powered relative to these training sample sizes, attaining AUCs of 0.66 for SCZ vs. rest, 0.64 for BIP vs. rest, 0.59 for MDD vs. rest, and 0.68 for control vs. rest. DDx-PRS produced comparable results to methods that leverage tuning data, confirming that DDx-PRS is an effective method. True diagnosis probabilities in top deciles of predicted diagnosis probabilities were considerably larger than prior baseline probabilities, particularly in projections to larger training sample sizes, implying considerable potential for clinical utility under certain circumstances. In conclusion, DDx-PRS is an effective method for distinguishing clinically related disorders.
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Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements-well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms-to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.
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Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants. We performed genome-wide association meta-analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified two novel loci associated with non-response to antidepressants and showed significant polygenic prediction in independent samples. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants.
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Creativity is known to be heritable and exhibits familial aggregation with psychiatric disorders; however, the complex nature of their relationship has not been well-established. In the present study, we demonstrate that using an expanded and validated machine learning (ML)-based phenotyping of occupational creativity (OC) can allow us to further understand the trait of creativity, which was previously difficult to define and study. We conducted the largest genome-wide association study (GWAS) on OC with 241,736 participants from the UK Biobank and identified 25 lead variants that have not yet been reported and three candidate causal genes that were previously associated with educational attainment and psychiatric disorders. We found extensive genetic overlap between OC and psychiatric disorders with mixed effect direction through various post-GWAS analyses, including the bivariate causal mixture model. In addition, we discovered a strongly genetic correlation between our original GWAS and the GWAS adjusted for education years (rg = 0.95). Our GWAS analysis via ML-based phenotyping contributes to the understanding of the genetic architecture of creativity, which may inform genetic discovery and genetic prediction in human cognition and psychiatric disorders.
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Estudio de Asociación del Genoma Completo , Trastornos Mentales , Humanos , Predisposición Genética a la Enfermedad , Trastornos Mentales/genética , Cognición , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).