Pharmacogenomics J. 2022 Jan 17. doi: 10.1038/s41397-021-00255-3. Online ahead of print.

ABSTRACT

Azathioprine (AZA) and its metabolite, mercaptopurine (6-MP), are widely used immunosuppressant drugs. Polymorphisms in genes implicated in AZA/6-MP metabolism, reportedly, could account in part for their potential toxicity. In the present study we performed a systematic review and a meta-analysis, comprising 30 studies and 3582 individuals, to investigate the putative genetic association of two inosine triphosphatase (ITPA) polymorphisms with adverse effects in patients treated with AZA/6-MP. We found that rs1127354 is associated with neutropenia in general populations and in children (OR: 2.39, 95%CI: 1.97-2.90, and OR: 2.43, 95%CI: 2.12-2.79, respectively), and with all adverse effects tested herein in adult populations (OR: 2.12, 95%CI: 1.22-3.69). We also found that rs7270101 is associated with neutropenia and leucopenia in all-ages populations (OR: 2.93, 95%CI: 2.36-3.63, and OR: 2.82, 95%CI: 1.76-4.50, respectively) and with all adverse effects tested herein in children (OR: 1.74, 95%CI: 1.06-2.87). Stratification according to background disease, in combination with multiple comparisons corrections, verified neutropenia to be associated with both polymorphisms, in acute lymphoblastic leukemia (ALL) patients. These findings suggest that ITPA polymorphisms could be used as predictive biomarkers for adverse effects of thiopurine drugs to eliminate intolerance in ALL patients and clarify dosing in patients with different ITPA variants.

PMID:35034963 | DOI:10.1038/s41397-021-00255-3

Adv Protein Chem Struct Biol. 2022;128:361-396. doi: 10.1016/bs.apcsb.2021.08.002. Epub 2021 Oct 13.

ABSTRACT

G protein-coupled receptors (GPCRs) are membrane proteins that play a central role in cell signaling and constitute one of the largest classes of drug targets. The molecular mechanisms underlying GPCR function have been characterized by several experimental and computational methods and provide an understanding of their role in physiology and disease. Population variants arising from nsSNPs affect the native function of GPCRs and have been implicated in differential drug response. In this chapter, we provide an overview on GPCR structure and activation, with a special focus on the β2-adrenergic receptor (β2-AR). First, we discuss the current understanding of the structural and dynamic features of the wildtype receptor. Subsequently, the population variants identified in this receptor from clinical and large-scale genomic studies are described. We show how computational approaches such as bioinformatics tools and molecular dynamics simulations can be used to characterize the variant receptors in comparison to the wildtype receptor. In particular, we discuss three examples of clinically important variants and discuss how the structure and function of these variants differ from the wildtype receptor at a molecular level. Overall, the chapter provides an overview of structure and function of GPCR variants and is a step towards the study of inter-individual differences and personalized medicine.

PMID:35034724 | DOI:10.1016/bs.apcsb.2021.08.002

Clin Pharmacol Ther. 2022 Jan 16. doi: 10.1002/cpt.2526. Online ahead of print.

ABSTRACT

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).

PMID:35034351 | DOI:10.1002/cpt.2526

Clin Pharmacol Ther. 2022 Jan 16. doi: 10.1002/cpt.2527. Online ahead of print.

ABSTRACT

SLCO1B1 genotype is known to influence patient adherence to statin therapy, in part by increasing the risk for statin-associated musculoskeletal symptoms (SAMS). The SLCO1B1*5 allele has previously been associated with simvastatin discontinuation and SAMS. Prior analyses of the relationship between SLCO1B1*5 and atorvastatin muscle side effects have been inconclusive due to insufficient power. We now quantify the impact of SLCO1B1*5 on atorvastatin discontinuation and SAMS in a large observational cohort using electronic medical record (EMR) data from a single health care system. In our study cohort (n = 1,627 patients exposed to atorvastatin during the course of routine clinical care), 56% (n = 912 of 1,627 patients) discontinued atorvastatin and 18% (n = 303 of 1,627 patients) developed SAMS. A univariate model revealed that SLCO1B1*5 increased the likelihood that patients would stop atorvastatin during routine care (Odds Ratio 1.2, 95% confidence interval [C.I.]: 1.1 - 1.5, p = 0.04). A multivariate Cox proportional hazards model further demonstrated that this same variant was associated with time to atorvastatin discontinuation (Hazard Ratio 1.2, C.I. 1.1 - 1.4, p = 0.004). Additional time-to-event analyses also revealed that SCLO1B1*5 was associated with SAMS (Hazard Ratio 1.4, C.I. 1.1 - 1.7, p = 0.02). Atorvastatin discontinuation was associated with SAMS (Odds Ratio 1.67, p = 0.0001) in our cohort.

PMID:35034348 | DOI:10.1002/cpt.2527

Pathol Res Pract. 2022 Jan 10;230:153760. doi: 10.1016/j.prp.2022.153760. Online ahead of print.

ABSTRACT

Next-generation sequencing (NGS) has been increasingly popular in genomics studies over the last decade, as new sequencing technology has been created and improved. Recently, NGS started to be used in clinical oncology to improve cancer therapy through diverse modalities ranging from finding novel and rare cancer mutations, discovering cancer mutation carriers to reaching specific therapeutic approaches known as personalized medicine (PM). PM has the potential to minimize medical expenses by shifting the current traditional medical approach of treating cancer and other diseases to an individualized preventive and predictive approach. Currently, NGS can speed up in the early diagnosis of diseases and discover pharmacogenetic markers that help in personalizing therapies. Despite the tremendous growth in our understanding of genetics, NGS holds the added advantage of providing more comprehensive picture of cancer landscape and uncovering cancer development pathways. In this review, we provided a complete overview of potential NGS applications in scientific and clinical oncology, with a particular emphasis on pharmacogenomics in the direction of precision medicine treatment options.

PMID:35033746 | DOI:10.1016/j.prp.2022.153760

Pharmacol Res. 2022 Jan 13:106087. doi: 10.1016/j.phrs.2022.106087. Online ahead of print.

ABSTRACT

Inter-individual variability in pharmacokinetics and drug response is heavily influenced by single-nucleotide variants (SNVs) and copy-number variations (CNVs) in genes with importance for drug disposition. Nowadays, a plethora of studies implement next generation sequencing to capture rare and novel pharmacogenomic (PGx) variants that influence drug response. To address these issues, we present a comprehensive end-to-end analysis workflow, beginning from targeted PGx panel re-sequencing to in silico analysis pipelines and in vitro validation assays. Specifically, we show that novel pharmacogenetic missense variants that are predicted or putatively predicted to be functionally deleterious, significantly alter protein activity levels of CYP2D6 and CYP2C19 proteins. We further demonstrate that variant priorization pipelines tailored with functional in vitro validation assays provide supporting evidence for the deleterious effect of novel PGx variants. The proposed workflow could provide the basis for integrating next-generation sequencing for PGx testing into routine clinical practice.

PMID:35033648 | DOI:10.1016/j.phrs.2022.106087

Trials. 2022 Jan 15;23(1):37. doi: 10.1186/s13063-022-05999-2.

ABSTRACT

INTRODUCTION: Hypertension is one of the most important risk factors for cardiovascular disease, and its control rates remain low worldwide. The most effective strategy is that patients with hypertension should be diagnosed and treated early. Preliminary studies showed that the Bushen Jiangya granule (BSJY) could suppress ventricular hypertrophy and inflammatory responses, lower blood pressure, and protect the target organs of hypertension. We designed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of BSJY in patients with low-to-medium risk hypertension.

METHODS AND ANALYSIS: This trial is a one-center, randomized, double-blind, placebo-controlled study. A total of 260 participants will be randomized in a 1:1 ratio to an experimental group (BSJY plus amlodipine) and a control group (placebo plus amlodipine). The trial cycle will last 8 weeks. The primary outcome is the change in 24-h average systolic and diastolic blood pressure. The secondary outcomes include heart rate variability, pharmacogenomic evaluation, improvement in TCM syndrome, and serum pro-inflammatory/anti-inflammatory cytokines between the two groups. The safety of medication will also be evaluated. All the data will be recorded in electronic case report forms and analyzed by SPSS V.22.0.

ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences in Beijing, China (No. 2019-186-KY-01). The participants are volunteers, understand the process of this trial, and sign an informed consent. The results of this study will be disseminated to the public through peer-reviewed journals and academic conferences.

DISCUSSION: We hypothesize that patients with low-to-medium-risk hypertension will benefit from BSJY. If successful, this study will provide evidence-based recommendations for clinicians.

TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiMCTR1900002876. Registered in November 2019.

PMID:35033168 | DOI:10.1186/s13063-022-05999-2

Diabetes Res Clin Pract. 2022 Jan 12:109193. doi: 10.1016/j.diabres.2022.109193. Online ahead of print.

ABSTRACT

AIMS: To examine the predictive factors associated with the progression of different prediabetic status to diabetes.

METHODS: A two-year retrospective cohort study was conducted on 5741 participants aged 40 years or older. Finally, 1685 participants with prediabetes defined by IFG (impaired fasting glucose), IGT (impaired glucose tolerance) and CGI (combined IFG and IGT) were included. Logistic regression model was used to evaluate the risk of prediabetes progression to diabetes.

RESULTS: Of the 1685 subjects with prediabetes at baseline, 212 (12.6%) subjects progressed to diabetes and 1473 (87.4%) subjects did not. Logistic regression analysis demonstrated that people with CGI were associated with an increased risk of progressing to diabetes compared to those with IFG (OR, 95% CI: 3.127, 2.047-4.776). Moreover, males, obese people, people with increased BMI and WHR (Waist/ Hip ratio), and hypertension were positively associated with the progression to diabetes, while HOMA-β was negatively associated with the progression to diabetes.

CONCLUSIONS: Subjects with CGI are prone to progressed to diabetes compared to those with IFG or IGT in middle-aged and older person in China. More attention should be paid to male and obese prediabetic subjects, and measures should be taken to control the increase in their BMI and WHR.

PMID:35032561 | DOI:10.1016/j.diabres.2022.109193

Expert Opin Drug Metab Toxicol. 2022 Jan 14. doi: 10.1080/17425255.2021.2029403. Online ahead of print.

ABSTRACT

INTRODUCTION: : Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied.

AREAS COVERED: : This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine.

EXPERT OPINION: : New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Pre-emptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.

PMID:35029518 | DOI:10.1080/17425255.2021.2029403

Artif Organs. 2022 Jan 14. doi: 10.1111/aor.14161. Online ahead of print.

ABSTRACT

BACKGROUND: Hemodialysis (HD) using super high-flux dialyzer (HD + SHF) comparably removed uremic toxins to high-volume postdilution online hemodiafiltration (olHDF). Integration of hemoperfusion (HP) to HD + SHF (HD + SHF + HP) might provide superior uremic toxin removing capability to high-volume postdilution olHDF.

METHOD: The present study was conducted in thrice-a-week HD patients to compare the efficacy in removing indoxyl sulfate (IS), beta-2 microglobulin (β2 M), and urea between high-volume postdilution ol-HDF and HD + SHF + HP, comprising HD + SHF as the main treatment plus HD + SHF + HP 1/week in the first 4 weeks and 1/2 weeks in the second 4 weeks.

RESULTS: Ten prevalent HD patients with blood flow rate (BFR) above 400 ml/min were randomized into two sequences of 8-week treatment periods of HD + SHF + HP and later high-volume postdilution olHDF or vice versa. When compared with high-volume postdilution olHDF (convective volume of 26.02 ± 1.8 L/session), HD + SHF + HP provided comparable values of percentage reduction ratio of IS (52.0 ± 11.7 vs. 56.3 ± 7.5%, p = 0.14) and β2 M (83.7 ± 4.9 vs. 84.0 ± 4.3%, p = 0.37) and slightly lower urea reduction ratio. Despite greater dialysate albumin loss (p = 0.008), there was no significant change in serum albumin level in HD + SHF + HP group.

CONCLUSIONS: HD + SHF + HP could not provide superior efficacy in removing uremic toxins to high-volume postdilution olHDF. The use of low BFR of 200 ml/min during the first 2 h of HD + SHF + HP session, according to the instruction of manufacturer, might impair the efficacy of the HD + SHF part in removing uremic toxins.

PMID:35028951 | DOI:10.1111/aor.14161

Semin Oncol. 2021 Dec 13:S0093-7754(21)00074-9. doi: 10.1053/j.seminoncol.2021.11.004. Online ahead of print.

ABSTRACT

BACKGROUND: Fluoropyrimidine chemotherapy is used across many tumor types and settings. The incidence of severe adverse events (SAEs) is around 20%. Mortality is 0.5%-1%. Dihydropyrimidine dehydrogenase (DPD) plays a key role in fluoropyrimidine inactivation. Key DPYD mutations are linked to a high risk of SAEs. Pretreatment DPD screening was mandated by EMA guidelines in April 2020 and widely adopted thereafter. Uncertainty remains regarding optimal dosing practice.

METHODS: We retrospectively examined records of all 23 patients with DPYD mutation who started chemotherapy between April and November 2020. Our center tests for the mutations considered clinically actionable by Clinical Pharmacogenetics Implementation Consortium and uses the Gene Activity Score (GAS) to guide dose reduction.

RESULTS: Most patients started on a 50% dose. One started on 100% and experienced mild diarrhea after cycle 2; DPD was tested belatedly, subsequent cycles were reduced to 50% and he remained well. Three patients receiving chemo-radiotherapy started on 76% dose; 50% was felt to be subtherapeutic. One of them had no toxicities; another had grade 2 nausea and a hospital attendance with non-neutropenic fever; the third was admitted for 6 weeks with pancolitis. Seven patients did not have toxicities above grade 1 and no hospital attendances. Five patients had further dose reductions. None had dose escalation.

CONCLUSION: As our experience shows, patients with DPD deficiency are heterogeneous. Worryingly, SAEs occur despite dose reduction according to GAS. Others had minimal toxicity and may be under-dosed by GAS. There are clearly many factors at play other than the 4 DPYD variants. The DPD result must be available and inform first cycle dosing. Dose should be cautiously titrated up if tolerated; this was not done at our center due to clinician caution. Further research is needed to guide this. Patients should be reviewed frequently, counselled regarding their DPD status, and empowered to seek advice promptly when they feel unwell.

PMID:35027218 | DOI:10.1053/j.seminoncol.2021.11.004

Metabolism. 2022 Jan 10:155121. doi: 10.1016/j.metabol.2021.155121. Online ahead of print.

NO ABSTRACT

PMID:35026232 | DOI:10.1016/j.metabol.2021.155121

Lancet Gastroenterol Hepatol. 2022 Feb;7(2):171-185. doi: 10.1016/S2468-1253(21)00223-5.

ABSTRACT

Therapeutic drug monitoring (TDM) has emerged as a useful tool for optimising the use of biologics, and in particular anti-tumour necrosis factor (anti-TNF) therapy, in inflammatory bowel disease (IBD). However, challenges remain and are hindering the widespread implementation of TDM in clinical practice. These barriers include identification of the optimal drug concentration to target, the lag time between sampling and results, and the proper interpretation of anti-drug antibody titres among different assays. Solutions to overcome these barriers include the harmonisation of TDM assays and the use of point-of-care testing. Other unmet needs include well designed prospective studies and randomised controlled trials focusing on proactive TDM, particularly during induction therapy. Future studies should also investigate the utility of TDM for biologics other than anti-TNF therapies in both IBD and other immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis, and the use of pharmacokinetic modelling dashboards and pharmacogenetics towards individual personalised medicine.

PMID:35026171 | DOI:10.1016/S2468-1253(21)00223-5

J Crohns Colitis. 2022 Jan 12:jjac004. doi: 10.1093/ecco-jcc/jjac004. Online ahead of print.

ABSTRACT

Exactly 70 years ago mercaptopurine (1951) was discovered by Gertrude Elion as a novel treatment option for acute leukemia. A total of three thiopurines (also thioguanine (1950) and azathioprine (1957)) were developed over time. These immunosuppressive drugs were also successfully introduced a few decades later to prevent rejection of transplanted organs and to treat several autoimmune diseases. For the discovery of thiopurines and other antimetabolite drugs she was rewarded in 1988, together with George Hitchings and James Black, with the Nobel Prize in Physiology or Medicine. Important steps have been made in recent years to unravel its metabolism, mode of action and pharmacogenetics. Till today thiopurine (based) therapy remains an essential immunosuppressive approach in treating patients with inflammatory bowel disease.

PMID:35024806 | DOI:10.1093/ecco-jcc/jjac004

Acta Pharm Sin B. 2021 Dec;11(12):3779-3790. doi: 10.1016/j.apsb.2021.11.022. Epub 2021 Dec 4.

ABSTRACT

PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

PMID:35024306 | PMC:PMC8727916 | DOI:10.1016/j.apsb.2021.11.022

Expert Opin Drug Metab Toxicol. 2022 Jan 13. doi: 10.1080/17425255.2021.2029406. Online ahead of print.

ABSTRACT

INTRODUCTION: Despite new treatment options for inflammatory bowel disease (IBD), conventional thiopurines remain a common treatment option for maintaining remission, particularly in non-Westernized countries. Therapeutic drug monitoring (TDM) is advised in standard care for optimizing therapy strategies to improve effectiveness, reveal nonadherence and reduce toxicity. Still, the rationale of TDM is debated.

AREAS COVERED: Key insights on TDM of thiopurine metabolites are discussed. The pharmacology of thiopurines is described, emphasizing the interindividual differences in pharmacogenetics, pharmacokinetics and pharmacodynamics. Pharmacological differences between conventional thiopurines and tioguanine are outlined. Finally, several optimization strategies for thiopurine therapy in IBD are discussed.

EXPERT OPINION: TDM has been a useful, but limited, tool to individualize thiopurine therapy. Pharmacokinetic data on the active thiopurine metabolites, derived from measurements in erythrocytes, associated with clinical response only partially predict effectiveness and toxicity. An additional pharmacodynamic marker, such as Rac1/pSTAT3 expression in leukocytes, may improve applicability of TDM in the future.

PMID:35023443 | DOI:10.1080/17425255.2021.2029406

Pharmacogenomics. 2022 Jan 13. doi: 10.2217/pgs-2021-0155. Online ahead of print.

ABSTRACT

Tweetable abstract Pharmacogenetic tests are a promising strategy to improve safety and effectiveness of HIV therapy. However, implementation can be challenging in populations with complex genetic structure.

PMID:35023374 | DOI:10.2217/pgs-2021-0155

Cancer Res. 2022 Jan 12:canres.2058.2021. doi: 10.1158/0008-5472.CAN-21-2058. Online ahead of print.

ABSTRACT

Enhancer RNAs (eRNA) regulate gene expression and play critical roles in cancer. Using large-scale omics data from The Cancer Genome Atlas (TCGA), we systematically investigated the impact of genetic variants on eRNA expression and identified ~1 million eRNA quantitative trait loci (eRNA-QTL) as cis- and trans-acting. Over 16,000 eRNA-QTLs were associated with patient overall survival. Assessing the impact of eRNAs on >1,000 imputed anti-cancer drug responses across ~10,000 cancer patients revealed > 7 million significant associations. Furthermore, ~240,000 significant associations were identified between eRNA expression and immune cell abundance deconvoluted by TIMER, CIBERSORT, ImmuCellAI, and ImmuneCellGSVA. Finally, a user-friendly data portal was generated: Genetic, Pharmacogenomic, and Immune landscapes of eRNAs (GPIeR, https://hanlab.tamhsc.edu/GPIeR/). GPIeR is a large-scale multi-dimensional data portal that can be used to explore eRNA-associated genetic variants, drug responses, and immune infiltration with the purpose of facilitating functional and clinical investigations of eRNAs in cancer.

PMID:35022213 | DOI:10.1158/0008-5472.CAN-21-2058

Haematologica. 2022 Jan 13. doi: 10.3324/haematol.2021.280305. Online ahead of print.

ABSTRACT

Not available.

PMID:35021610 | DOI:10.3324/haematol.2021.280305

JAMA Psychiatry. 2022 Jan 12. doi: 10.1001/jamapsychiatry.2021.3799. Online ahead of print.

ABSTRACT

IMPORTANCE: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts.

OBJECTIVE: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples.

DESIGN, SETTING, AND PARTICIPANTS: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]).

MAIN OUTCOMES AND MEASURES: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition.

RESULTS: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04).

CONCLUSIONS AND RELEVANCE: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.

PMID:35019943 | DOI:10.1001/jamapsychiatry.2021.3799