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and the Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) 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. RESULTSThe 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 (r 2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r 2 = 1.09%; P = .04). CONCLUSIONS AND RELEVANCEIn 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 patie...
Introduction: Despite the increased utilization of pharmacogenetic (PGt) testing to guide drug therapy, little is known about the ethical challenges posed by the use of these genetic tools. Methods: This cross-sectional study aimed to address ethical issues related to ancillary genetic information, consent forms, and potential confidentiality breaches from physicians' perspectives. A questionnaire was administered to all practicing physicians working in KAUH. Results: Almost 49% and 65% of physicians were willing to recommend PGt testing for adult and pediatric patients, respectively. The findings showed that physicians attitudes towards the clinical utility of PGt testing became more preceptive. The majority (73.7%) indicated that PGt testing should not be treated as other routine laboratory tests. The finding also focused on potential conflicts regarding ancillary genetic information, in which 78.8% indicated that they would like to preserve the confidentiality and privacy of the patients and only 14.4% of physicians did not feel obligated to let patients know about any future risk that might be uncovered using PGt testing. The findings showed that collecting both verbal and written consents was imperative prior to testing. Seriousness and predictability of the diseases were reported to be legitimate circumstances that allow disclosure of genetic information. Discussion: Unless the field of PGt testing addresses the ethical challenges that might be encountered during PGt treatment, these issues might influence its acceptance in routine clinical settings. Establishing a minimal set of ethical standards may help emphasize the role of physicians and thus facilitate the implementation of PGt tests.
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