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[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., This work was supported by Medical Research Council Centre grant MR/L010305/1, Medical Research Council Program grant MR/P005748/1, and Medical Research Council Project grants MR/L011794/1 and MC_PC_17212 to Cardiff University and by the National Centre for Mental Health, funded by the Welsh Government through Health and Care Research Wales. This work acknowledges the support of the Supercomputing Wales project, which is partially funded by the European Regional Development Fund via the Welsh Government. Dr Pardiñas was supported by an Academy of Medical Sciences Springboard Award (SBF005\1083). Dr Andreassen was supported by the Research Council of Norway (grants 283798, 262656, 248980, 273291, 248828, 248778, and 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, and the European Union’s Horizon 2020 Research and Innovation Programme (grant 847776). Dr Ajnakina was supported by an National Institute for Health Research postdoctoral fellowship (PDF-2018-11-ST2-020). Dr Joyce was supported by the University College London Hospitals/UCL University College London Biomedical Research Centre. Dr Kowalec received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement (793530) from the government of Canada Banting postdoctoral fellowship programme and the University of Manitoba. Dr Sullivan was supported by the Swedish Research Council (Vetenskapsrådet, D0886501), the European Union’s Horizon 2020 programme (COSYN, 610307) and the US National Institute of Mental Health (U01 MH109528 and R01 MH077139). The Psychiatric Genomics Consortium was partly supported by the National Institute Of Mental Health (grants R01MH124873). The Sweden Schizophrenia Study was supported by the National Institute Of Mental Health (grant R01MH077139). The STRATA consortium was supported by a Stratified Medicine Programme grant to Dr MacCabe from the Medical Research Council (grant MR/L011794/1), which funded the research and supported Drs Pardiñas, Smart, Kassoumeri, Murray, Walters, and MacCabe. Dr Smart was supported by a Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital National Health Service Foundation Trust. The AESOP (US) cohort was funded by the UK Medical Research Council (grant G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Genetics and Psychosis project (London, UK) cohort was funded by the UK National Institute of Health Research Specialist Biomedical Research Centre for Mental Health, South London and the Maudsley National Health Service Mental Health Foundation Trust (SLAM) and the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community’s Seventh Framework program (HEALTH-F2-2009-241909, project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (grants 320030_135736/1, 320030-120686, 324730-144064, 320030-173211, and 171804); the National Center of Competence in Research Synaptic Bases of Mental Diseases from the Swiss National Science Foundation (grant 51AU40_125759); and Fondation Alamaya. The Oslo (Norway) cohort was funded by the Research Council of Norway (grant 223273/F50, under the Centers of Excellence funding scheme, 300309, 283798) and the South-Eastern Norway Regional Health Authority (grants 2006233, 2006258, 2011085, 2014102, 2015088, and 2017-112). The Paris (France) cohort was funded by European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (grant NU20-04-00393). The Santander (Spain) cohort was funded by the following grants to Dr Crespo-Facorro: Instituto de Salud Carlos III (grants FIS00/3095, PI020499, PI050427, and PI060507), Plan Nacional de Drogas Research (grant 2005-Orden sco/3246/2004), SENY Fundatio Research (grant 2005-0308007), Fundacion Marques de Valdecilla (grant A/02/07, API07/011) and Ministry of Economy and Competitiveness and the European Fund for Regional Development (grants SAF2016-76046-R and SAF2013-46292-R). The West London (UK) cohort was funded by The Wellcome Trust (grants 042025, 052247, and 064607).

BACKGROUND: The 'jumping to conclusions' (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ.; METHODS: A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.; RESULTS: The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score was non-significantly associated with a higher number of beads drawn (B = 0.47, 95% CI -0.21 to 1.16, p = 0.17); whereas IQ PRS (B = 0.51, 95% CI 0.25-0.76, p < 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ (B = -1.7, 95% CI -2.8 to -0.5, p = 0.006), but did not relate to delusions in patients.; CONCLUSIONS: Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.

Additional file 1. Reports details on the sample composition, and particularly, the overlap between samples; details concerning the main analyses (e.g. effects that were not of primary interest; unstandardized effects); and results from post-hoc analyses where the models of the study by van de Leemput et al. [4] and models of the current study are compared and fitted to both datasets.

Description of limited multiverse analysis.

Background: There is considerable evidence that many complex traits have a partially shared genetic basis, termed pleiotropy. It is therefore useful to consider integrating genome-wide association study (GWAS) data across several traits, usually at the summary statistic level. A major practical challenge arises when these GWAS have overlapping subjects. This is particularly an issue when estimating pleiotropy using methods that condition the significance of one trait on the signficance of a second, such as the covariate-modulated false discovery rate (cmfdr). Results: We propose a method for correcting for sample overlap at the summary statistic level. We quantify the expected amount of spurious correlation between the summary statistics from two GWAS due to sample overlap, and use this estimated correlation in a simple linear correction that adjusts the joint distribution of test statistics from the two GWAS. The correction is appropriate for GWAS with case-control or quantitative outcomes. Our simulations and data example show that without correcting for sample overlap, the cmfdr is not properly controlled, leading to an excessive number of false discoveries and an excessive false discovery proportion. Our correction for sample overlap is effective in that it restores proper control of the false discovery rate, at very little loss in power. Conclusions: With our proposed correction, it is possible to integrate GWAS summary statistics with overlapping samples in a statistical framework that is dependent on the joint distribution of the two GWAS.

cite as: Lataster, J., Collip, D., Ceccarini, J., Haas, D., Booij, L., van Os, J., Pruessner, J., Van Laere, K., & Myin-Germeys, I. (2011). Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: a positron emission tomography study using [18F] fallypride. Neuroimage, 58(4), 1081-1089.DOI: 10.1016/j.neuroimage.2011.07.030AbstractRodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D2/3 PET radioligand [18F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD = 15.8) underwenta single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD = 10.2) MBq [18F]fallypride. Psychosocial stress was initiated at 100minutes postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [18F]fallypride displacement.Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone.

see alsoLataster, J., Collip, D., Ceccarini, J., Haas, D., Booij, L., van Os, J., ... & Myin-Germeys, I. (2011). Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: a positron emission tomography study using [18F] fallypride. Neuroimage, 58(4), 1081-1089.DOI: 10.1016/j.neuroimage.2011.07.030Rodent studies suggest that prefrontal dopamine neurotransmission plays an important role in the neural processing of psychosocial stress. Human studies investigating stress-induced changes in dopamine levels, however, have focused solely on striatal dopamine transmission. The aim of this study was to investigate in vivo dopamine release in the human prefrontal cortex in response to a psychosocial stress challenge, using the highly selective dopamine D₂/₃ PET radioligand [¹⁸F]fallypride in healthy subjects. Twelve healthy subjects (age (y): 39.8; SD=15.8) underwent a single dynamic Positron Emission Tomography (PET) scanning session after intravenous administration of 185.2 (SD=10.2) MBq [¹⁸F]fallypride. Psychosocial stress was initiated at 100 min postinjection. PET data were analyzed using the linearized simplified reference region model (LSRRM), which accounts for time-dependent changes in [¹⁸F]fallypride displacement. Voxel-based statistical maps, representing specific D₂/₃ binding changes, were computed to localize areas with increased ligand displacement after task initiation, reflecting dopamine release. The psychosocial stress challenge induced detectable amounts of dopamine release throughout the prefrontal cortex, with dopaminergic activity in bilateral ventromedial prefrontal cortex being associated with subjectively rated experiences of psychosocial stress. The novel finding that a mild psychosocial stress in humans induces increased levels of endogenous dopamine in the PFC indicates that the dynamics of the dopamine-related stress response cannot be interpreted by focusing on mesolimbic brain regions alone.

BackgroundPsychotic reactivity to stress has been shown to be dependent from an interaction between (i) genetically and environmentally predisposed vulnerabilities, and (ii) the impact of environmental changes experienced as stressful. The underlying biological mechanisms and the origins of this sensitization to stress, resulting in psychotic experiences, are however unknown.Promising neurobiological candidates that may mediate psychotic reactivity to stress are an abnormal hypothalamic-pituitary-adrenal (HPA) axis reactivity as well as dysfunctional dopamine reactivity. Possible origins of psychotic reactivity to stress are expected to be related to genetic polymorphisms associated with psychosis, stress-reactivity, and HPA-axis functioning. In the current study we will be investigating the phenomenology, underlying biological mechanisms, and related genetic polymorphisms of psychotic reactivity to stress.MethodsTo cover different intensities of the psychotic spectrum, three groups, including unmedicated psychotic patients, first-degree relatives of patients and subjects psychometrically at risk for psychosis, will be compared to healthy control subjects with no history of psychosis.A repeated momentary self-assessment technique (Experience Sampling Method; ESM) in combination with an experimental psychosocial stress task will be used to evaluate psychotic reactivity to stress.Positron Emission Tomography (PET) will be utilized as an imaging tool to assess dopaminergic neurotransmission in response to experimentally induced psychosocial stress. In addition, cortisol measurements, as an indicator of HPA-axis functioning, will be monitored during experimental and daily life stressors. Finally, gene polymorphism data are collected through saliva sampling.HypothesesWe hypothesize that (i) the level of psychotic reactivity is different between subject-groups, (ii) psychotic reactivity is mediated by biological reactivity (cortisol, dopamine) and will differ between groups, (iii) the level of psychotic reactivity is influenced by genetic polymorphisms and early trauma and will differ between groups.see also:Lataster, J., Myin‐Germeys, I., Lieb, R., Wittchen, H. U., & van Os, J. (2012). Adversity and psychosis: a 10‐year prospective study investigating synergism between early and recent adversity in psychosis. Acta psychiatrica scandinavica, 125(5), 388-399.DOI: 10.1111/j.1600-0447.2011.01805.xLataster, J., Collip, D., Ceccarini, J., Hernaus, D., Haas, D., Booij, L., ... & Myin-Germeys, I. (2013). Familial liability to psychosis is associated with attenuated dopamine stress signaling in ventromedial prefrontal cortex. Schizophrenia bulletin, 40(1), 66-77.DOI: 10.1093/schbul/sbs187Lataster, J., Collip, D., Ceccarini, J., Haas, D., Booij, L., van Os, J., ... & Myin-Germeys, I. (2011). Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: a positron emission tomography study using [18 F] fallypride. Neuroimage, 58(4), 1081-1089.DOI: 10.1016/j.neuroimage.2011.07.030Collip, D., Nicolson, N. A., Lardinois, M., Lataster, T., Van Os, J., & Myin-Germeys, I. (2011). Daily cortisol, stress reactivity and psychotic experiences in individuals at above average genetic risk for psychosis. Psychological medicine, 41(11), 2305-2315.Collip, D., Myin-Germeys, I., Wichers, M., Jacobs, N., Derom, C., Thiery, E., ... & Van Os, J. (2013). FKBP5 as a possible moderator of the psychosis-inducing effects of childhood trauma. The British Journal of Psychiatry, 202(4), 261-268.Collip, D., van Winkel, R., Peerbooms, O., Lataster, T., Thewissen, V., Lardinois, M., ... & Myin‐Germeys, I. (2011). COMT Val158Met–stress interaction in psychosis: role of background psychosis risk. CNS neuroscience & therapeutics, 17(6), 612-619.Collip, D., Myin-Germeys, I., & Van Os, J. (2008). Does the concept of “sensitization” provide a plausible mechanism for the putative link between the environment and schizophrenia?. Schizophrenia bulletin, 34(2), 220-225.

Patients diagnosed with a psychotic disorder and their first-degree relatives display increased reactivity to stress. Although experience of psychosocial stress is associated both with ventromedial prefrontal and mesolimbic dopamine neurotransmission, the role of prefrontal dopamine transmission in the stress psychosis phenotype remains underresearched. The current study aimed at investigating stress-induced in vivo dopamine release in ventromedial prefrontal cortex (vmPFC) of individuals at familial risk for psychosis. first-degree relatives of patients with a psychotic disorder displayed attenuated dopamine stress neuromodulation in vmpfC, possibly reflecting reduced prefrontal regulation of stress-induced mesolimbic dopamine release.see alsoLataster, J., Collip, D., Ceccarini, J., Hernaus, D., Haas, D., Booij, L., ... & Myin-Germeys, I. (2013). Familial liability to psychosis is associated with attenuated dopamine stress signaling in ventromedial prefrontal cortex. Schizophrenia bulletin, 40(1), 66-77.DOI: 10.1093/schbul/sbs187

see alsoLataster, J., Myin‐Germeys, I., Lieb, R., Wittchen, H. U., & Van Os, J. (2012). Adversity and psychosis: a 10‐year prospective study investigating synergism between early and recent adversity in psychosis. Acta psychiatrica scandinavica, 125(5), 388-399.DOI: 10.1111/j.1600-0447.2011.01805.xObjective: Recent studies have suggested that early adverse events, such as childhood trauma, may promote enduring liability for psychosis whereas more recent adverse events may act as precipitants. Examination of these environmental dynamics, however, requires prospective studies in large samples. This study examines whether the association between recent adverse events and psychosis is moderated by exposure to early adversity.Method: A random regional representative population sample of 3021 adolescents and young adults in Munich, Germany, was assessed three times over a period of up to 10 years, collecting information on sociodemographic factors, environmental exposures, and measures of psychopathology and associated clinical relevance. Evidence of statistical non-additivity between early adversity (two levels) and more recent adversity (four levels) was assessed in models of psychotic symptoms. Analyses were a priori corrected for age, gender, cannabis use, and urbanicity.Results: Early and recent adversity were associated with each other (RR = 1.32, 95% CI 1.06–1.66; P = 0.014) and displayed statistical non-additivity at the highest level of exposure to recent adversity (χ2 = 4.59; P = 0.032).Conclusion: The findings suggest that early adversity may impact on later expression of psychosis either by increasing exposure to later adversity and/or by rendering individuals more sensitive to later adversity if it is severe.