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European Community, FP7 [HEALTH-F2-2009-241909]; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III [SAM16PE07CP1, PI16/02012, PI19/024]; CIBERSAM; Madrid Regional Government [B2017/BMD-3740 AGES-CM-2]; Fundación Familia Alonso and Fundación Alicia Koplowitz, Fusar-Poli, L., Pries, L.-K., van Os, J., Radhakrishnan, R., Pençe, A.Y., Erzin, G., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Üçok, A., Alptekin, K., Saka, M.C., Aguglia, E., Arango, C., Rutten, B.P., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

The EUGEI project was supported by the European Community's Seventh Framework Program under grant agreement No. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O'Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/L010305/1), Henquet, C., Van Os, J., Pries, L.K., Rauschenberg, C., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.S., Kaymak, S.U., Mihaljevic, M.M., Petrovic, S.S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., Atbaşoelu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M., Rutten, B.P.F., Gülöksüz, S.

BackgroundThere is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.MethodsWe analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.ResultsThe impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: −0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).ConclusionsThe results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.

European Community's Seventh Framework Program, European Commission [HEALTH-F2-2009-241909]; Scientific and Technological Research Council of Turkey, 2219 International Postdoctoral Research Fellowship Program; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, and PI19/024)..., Erzin, G., Pries, L.-K., van Os, J., Fusar-Poli, L., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M.C., Rutten, B.P.F., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

Hypothalamic–pituitary–adrenal (HPA) axis activity mediates the relationship between childhood trauma (CT) and psychosis. The FKBP5 gene, one of the key regulators of HPA axis activity after stress exposure, has been found associated with psychosis. Allele-specific and CT related FKBP5 demethylation in intron 7 was revealed in different psychiatric disorders. However, no studies have investigated FKBP5 methylation in subjects with different genetic liability for psychosis. A total of 144 participants were included in the study: 48 patients with psychotic disorders, 50 unaffected siblings, and 46 healthy controls. CT was assessed by Childhood Trauma Questionnaire. The FKBP5 rs1360780 was genotyped and FKBP5 methylation analyses were performed using bisulfite conversion followed by Sanger sequencing at three CpG sites in intron 7. Mixed linear model was used to assess group differences depending on rs1360780 T allele and CT. Results showed a significant T allele-dependent decrease of FKBP5 methylation in patients compared to unaffected siblings and controls. Effect of interaction between T allele and CT exposure on FKBP5 demethylation was found in controls. No effect of both risk factors (T allele and CT) on FKBP5 methylation level was found in unaffected siblings. We confirmed previous evidence of the association between the FKBP5 rs1360780 T allele, CT, and decreased FKBP5 methylation in intron 7. Allele-specific FKBP5 demethylation found in patients could shed a light on altered HPA axis activity in a subgroup of patients related to stress-induced psychosis. FKBP5 methylation and potential protective mechanisms in unaffected siblings after trauma exposure require further investigation. © 2021 Elsevier Ltd

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement No. HEALTH-F2- 2009-241909 (Project EU-GEI). Dr. Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16-PE07CP1, PI16/02012, PI19/024); CIBERSAM (...), Fusar-Poli, L; Pries, LK; van Os, J; Erzin, G; Delespaul, P; Kenis, G; Luykx, JJ; Lin, BCD; Richards, AL; Akdede, B; Binbay, T; Altinyazar, V; Yalincetin, B; Gumus-Akay, G; Cihan, B; Soygur, H; Ulas, H; Cankurtaran, ES; Kaymak, SU; Mihaljevic, MM; Andric-Petrovic, S; Mirjanic, T; Bernardo, M; Mezquida, G; Amoretti, S; Bobes, J; Saiz, PA; Garcia-Portilla, MP; Sanjuan, J; Aguilar, EJ; Santos, JL; Jimenez-Lopez, E; Arrojo, M; Carracedo, A; Lopez, G; Gonzalez-Penas, J; Parellada, M; Maric, NP; Atbasoglu, C; Ucok, A; Alptekin, K; Saka, MC; Aguglia, E; Arango, C; O'Donovan, M; Rutten, BPF; Guloksuz, S

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement no. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O’Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/ L010305/1). Dr Rutten was funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation. Drs Guloksuz and van Os are supported by the Ophelia research project, ZonMw grant number: 636340001. Dr Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024); CIBERSAM; Madrid Regional Government (B2017/BMD-3740, AGES-CM-2); Fundación Familia Alonso and Fundación Alicia Koplowitz., Pries, L.-K., Dal Ferro, G.A., Van Os, J., Delespaul, P., Kenis, G., Lin, B.D., Luykx, J.J., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Åžahin Cankurtaran, E., Ulusoy Kaymak, S., Mihaljevic, M.M., Andric Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., AtbaşoÄalu, C., Ucok, A., Alptekin, K., Can Saka, M., Arango, C., O'Donovan, M., Tosato, S., Rutten, B.P.F., Guloksuz, S., and Genetic Risk and Outcome of Psychosis (GROUP) investigators

Alterations in general intellectual ability and social cognition in schizophrenia are core features of the disorder, evident at the illness’ onset and persistent throughout its course. However, previous studies examining cognitive alterations in siblings discordant for schizophrenia yielded inconsistent results. Present study aimed to investigate the nature of the association between facial emotion recognition and general IQ by applying genetically sensitive cross-trait cross-sibling design. Participants (total n=158; patients, unaffected siblings, controls) were assessed using the Benton Facial Recognition Test, the Degraded Facial Affect Recognition Task (DFAR) and the Wechsler Adult Intelligence Scale-III. Patients had lower IQ and altered facial emotion recognition in comparison to other groups. Healthy siblings and controls did not significantly differ in IQ and DFAR performance, but siblings exhibited intermediate angry facial expression recognition. Cross-trait within-subject analyses showed significant associations between overall DFAR performance and IQ in all participants. Within-trait cross-sibling analyses found significant associations between patients’ and siblings’ IQ and overall DFAR performance, suggesting their familial clustering. Finally, cross-trait cross-sibling analyses revealed familial covariation of facial emotion recognition and IQ in siblings discordant for schizophrenia, further indicating their familial etiology. Both traits are important phenotypes for genetic studies and potential early clinical markers of schizophrenia-spectrum disorders.

BackgroundFirst-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.MethodsWe conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.ResultsIn both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.ConclusionsThe degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.

Aim To determine duration of untreated psychosis (DUP) in patients with schizophrenia-spectrum disorders from Serbia and to analyse factors that potentially contribute to the treatment delay, with focus on personality traits. Methods Fifty seven patients (males 54.4%; age = 29.9 ± 6.0 yrs; age at the illness onset = 24.9 ± 5.1 yrs; IQ = 93.5 ± 12.2) were included. The assessment consisted of Nottingham Onset Schedule (NOS), Premorbid Adjustment Scale (PAS) and NEO Personality Inventory (NEO-PI-R). We used Cox regression model to evaluate relationship between DUP and explanatory variables. Results Based on the most restrictive definition, the length of DUP in our sample was 77.8 ± 120.6 weeks (MED = 25.0 weeks). DUP was negatively associated with openness to experience (B = −0.804, P = 0.024). Conclusions We report the first evidence of DUP in Serbia, emphasizing that the personality domains are likely to impact the use of mental health care in persons with psychosis.

Aim The aim of the present study was to examine whether healthy individuals with higher levels of neuroticism, a robust independent predictor of psychopathology, exhibit altered facial emotion recognition performance. Methods Facial emotion recognition accuracy was investigated in 104 healthy adults using the Degraded Facial Affect Recognition Task (DFAR). Participants' degree of neuroticism was estimated using neuroticism scales extracted from the Eysenck Personality Questionnaire and the Revised NEO Personality Inventory. Results A significant negative correlation between the degree of neuroticism and the percentage of correct answers on DFAR was found only for happy facial expression (significant after applying Bonferroni correction). Conclusions Altered sensitivity to the emotional context represents a useful and easy way to obtain cognitive phenotype that correlates strongly with inter-individual variations in neuroticism linked to stress vulnerability and subsequent psychopathology. Present findings could have implication in early intervention strategies and staging models in psychiatry.

Increased reactivity to stress is observed in patients with schizophrenia spectrum disorders and their healthy siblings in comparison with the general population. Additionally, higher levels of neuroticism, as a proposed psychological measure of stress sensitivity, increase the risk of schizophrenia. HPA axis dysregulation is one of the possible mechanisms related to the vulnerability-stress model of schizophrenia, and recent studies revealed a possible role of the functional genetic variants of FK506-binding protein 51 (FKBP5) gene which modulate activity of HPA axis. The purpose of the present study was to investigate impact of FKBP5 on schizophrenia in Serbian patients and to explore relationship between genetic variants and neuroticism by using the case-sibling-control design. In 158 subjects, we measured psychotic experiences, childhood trauma and neuroticism. Nine single-nucleotide polymorphisms (rs9295158, rs3800373, rs9740080, rs737054, rs6926133, rs9380529, rs9394314, rs2766533 and rs12200498) were genotyped. The genetic influence was modeled using logistic regression, and the relationship between genetic variants and neuroticism was assessed by linear mixed model. Our results revealed genetic main effect of FKBP5 risk alleles (A allele of rs9296158 and T allele of rs3800373) and AGTC "risk" haplotype combination (rs9296158, rs3800373, rs9470080 and rs737054, respectively) on schizophrenia, particularly when childhood trauma was set as a confounding factor. We confirmed strong relationship between neuroticism and psychotic experiences in patients and siblings and further showed relationship between higher levels of neuroticism and FKBP5 risk variants suggesting potential link between biological and psychosocial risk factors. Our data support previous findings that trauma exposure shapes FKBP5 impact on schizophrenia.

Background: Epigenetic changes of the FKBP5 locus in adults were reported to be allele specific and trauma related in different patient populations. However, DNA methylation status of FKBP5 and its relation to the circulating protein levels are still unknown in schizophrenia spectrum disorders.

Background Hypothalamic–pituitary–adrenal (HPA) axis dysregulation is a potential neurobiological mechanism proposed by vulnerability-stress model for schizophrenia. Recent studies highlighted the role of functional genetic variants of FKBP5 gene, which affect the activity of HPA axis following stress exposure, and supported the hypothesis of increased stress sensitivity in schizophrenia. Additionally, FKBP5 demethylation in Intron 7 was observed in stress-related conditions thus the purpose of this pilot study was to investigate FKBP5 methylation levels at Intron 7 in schizophrenia. Methods Ethnically homogeneous Serbian sample of 24 schizophrenia spectrum patients and 24 controls matched by age and gender with patients’ group, were analyzed regarding DNA methylation levels at three CpG sites and average methylation level in Intron 7. Accordingly, we covered the area of GRE that has been reported to be associated with altered stress responsiveness. Epigenetic changes in FKBP5 Intron 7 were measured by Sanger sequencing and compared between the groups using t test as appropriate. Results Analyses revealed decreased FKBP5 methylation at the three targeted CpG sites (CpG1, CpG2, and CpG3) in patients compared to controls (p=0.026, p=0.017, and p=0.027, respectively). Similarly, when we averaged methylation scores of the observed region in Intron 7, significant demethylation was detected in patients (p=0.003). Discussion To the best of our knowledge this is the first study which explored FKBP5 epigenetic changes in schizophrenia. Conclusively to previous stress-related conditions, our preliminary results revealed significant decrease of FKBP5 methylation levels in Intron 7 in patients with schizophrenia. FKBP5 demethylation presents further insight into the reported FKBP5 genetic influence in psychosis and could be promising terapeutic target for the prevention of the onset and the course of schizophrenia.

To determine duration of untreated psychosis (DUP) in patients with schizophrenia-spectrum disorders from Serbia and to analyse factors that potentially contribute to the treatment delay, with focus on personality traits.Fifty seven patients (males 54.4%; age = 29.9 ± 6.0 yrs; age at the illness onset = 24.9 ± 5.1 yrs; IQ = 93.5 ± 12.2) were included. The assessment consisted of Nottingham Onset Schedule (NOS), Premorbid Adjustment Scale (PAS) and NEO Personality Inventory (NEO-PI-R). We used Cox regression model to evaluate relationship between DUP and explanatory variables.Based on the most restrictive definition, the length of DUP in our sample was 77.8 ± 120.6 weeks (MED = 25.0 weeks). DUP was negatively associated with openness to experience (B = -0.804, P = 0.024).We report the first evidence of DUP in Serbia, emphasizing that the personality domains are likely to impact the use of mental health care in persons with psychosis.

Introduction: It has been shown that depolarization disorders, autonomic dysfunction, and systolic dysfunction of the left ventricle are associated with sudden cardiac death after myocardial infarction. Objective: The Objective of study was to examine the prognostic value of the most important predictors in the first week after myocardial infarction. Method: Study included 881 patients who were followed up from 1 to 60 months. During the first week after myocardial infarction, following examination were performed: ECG with standard leads and X, Y, Z orthogonal leads, vectorcardiogram, QT interval, late potentials, short-time spectral analysis of RR variability, nonlinear (Poincare plot) analysis and echocardiogram. Results: In univariate analysis, the following parameters measured on the first day were important predictors of sudden cardiac death: lower LF/HF ratio(

IntroductionCurrent knowledge about the advantages of using split version of GAF scale – having separate Symptom (GAF-S) and Functioning (GAF-F) subscales is insufficient and has number of gaps. Present study analyzed the manner in which young adult remitted psychotic patients with different functional levels vary in their symptom severity and how GAF-F reflects presence/absence of well-known psychosis risk factors.MethodsSample comprised 37 remitted psychotic patients (56.8% male, 29.4 ± 6.1 years), categorized based on GAF-F scores into groups: ‘Moderate remission’ (GAF-F 41–60, n = 19) and “Good remission” (GAF-F > 61, n = 18). Participants were assessed using the GAF-S, WAIS-R, Nottingham Onset Schedule, Premorbid Adjustment and Brief Core Schema scales, childhood trauma and bullying questionnaires. Mann–Whitney and Student's t-tests were used to assess between-group differences.ResultsGroups did not differ in age, sex and education. When compared to “Good remission” group, “Moderate remission” group exhibited earlier illness’ onset (P = 0.01), greater symptom severity (P = 0.00), negative self-evaluation (P = 0.02), more childhood physical abuse (P = 0.01) and bullying (P = 0.01). Moreover, trend-like significances (P = 0.08) were observed for poorer adolescence adjustment and negative evaluation of others. There were no between-group differences regarding IQ and duration of untreated/treated illness.ConclusionsGAF scale is in the continual use since early 1990, however, evidence of further development of the instrument itself is sparse. Present research is demonstrating that GAF-F scores reflect diverse factors related to psychosis risk, the illness’ course and quality of remission. Moreover, the results contribute to surmount some of the gaps in knowledge about the split version of GAF scale.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Background: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is a proposed etiological mechanism of psychosis. Recent studies highlighted impact of the FKBP5 gene and its functional variant rs1360780, which risk (T) allele affects the activity of HPA axis following stress exposure, on psychotic patients exposed to early trauma (1). Additionally, risk allele and trauma dependent FKBP5 demethylation in intron 7 was observed in traumatized individuals (2). Thus, the purpose of this pilot study was to investigate influence of the risk allele and trauma on FKBP5 DNA methylation levels at intron 7 in psychotic patients and to compare it with healthy individuals. Methods: The sample consisted of 24 psychosis spectrum patients and 24 controls matched by age and gender. All participants were genotyped for rs1360780 and divided into 2 groups depending on the presence of the risk allele (risk and nonrisk group). DNA methylation levels at 3 CpG sites (CpG1, CpG2, and CpG3) in intron 7 were analyzed by Sanger sequencing. Early-life adversities were measured by Childhood Trauma Questionnaire. Pearson correlation and t test were performed as appropriate. Results: Analyses revealed decreased FKBP5 methylation at targeted CpG sites and averaged methylation level (AML) at intron 7 in patients compared to controls (P = .026, P = .017, P = .027, and P = .003, respectively). Decreased AML and methylation at CpG3 were observed comparing risk and nonrisk patients’ groups (P = .018 and P = .016, respectively). Additionally, decreased methylation was found in risk patients’ group compared to risk controls’ group. No differences were found comparing nonrisk groups. Furthermore, strong negative associations between trauma and methylation at CpG3 and AML were observed only in risk controls’ group (r = −0.707, P = .007; r = −0.741, P = .004, respectively). Conclusion: Our preliminary results revealed allele-specific epigenetic changes of the FKBP5 gene in psychotic patients, which is in line with previous reports in traumatized individuals. Trauma-related demethylation in risk controls’ group supports the hypothesis that psychotic and stress-related conditions could share common neurobiological underlying mechanism, such as HPA axis dysregulation, particularly in individuals with genetic predisposition for altered stress response.References1.Daskalakis NP, Binder EB. Schizophrenia in the spectrum of gene-stress interactions: the FKBP5 example. Schizophr Bull. 2015;41:323–329.2.Klengel T, Mehta D, Anacker C et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16:33–41.

The aim of the present study was to examine whether healthy individuals with higher levels of neuroticism, a robust independent predictor of psychopathology, exhibit altered facial emotion recognition performance.Facial emotion recognition accuracy was investigated in 104 healthy adults using the Degraded Facial Affect Recognition Task (DFAR). Participants' degree of neuroticism was estimated using neuroticism scales extracted from the Eysenck Personality Questionnaire and the Revised NEO Personality Inventory.A significant negative correlation between the degree of neuroticism and the percentage of correct answers on DFAR was found only for happy facial expression (significant after applying Bonferroni correction).Altered sensitivity to the emotional context represents a useful and easy way to obtain cognitive phenotype that correlates strongly with inter-individual variations in neuroticism linked to stress vulnerability and subsequent psychopathology. Present findings could have implication in early intervention strategies and staging models in psychiatry.

European Community Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G x E), however, so far, thorough replication of findings is rare and G x E research still faces several conceptual and methodological challenges. in this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G x E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G x E in schizophrenia. While such investigations are now well underway, new challenges emerge for G x E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. Maastricht Univ, Med Ctr, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci,South Limburg Mental H, NL-6200 MD Maastricht, Netherlands Kings Coll London, Inst Psychiat, Dept Psychosis Studies, London WC2R 2LS, England Mondriaan Mental Hlth Trust, Maastricht, Heerlen, Netherlands Univ Groningen, Univ Med Ctr Groningen, Rob Giel Clin Res, Univ Ctr Psychiat, Groningen, Netherlands Kings Coll London, Inst Psychiat, Dept Hlth Serv & Populat Res, London WC2R 2LS, England Kings Coll London, Inst Psychiat, Dept Psychol, London WC2R 2LS, England Cardiff Univ, MRC, Ctr Neuropsychiat Genet, Cardiff CF10 3AX, S Glam, Wales Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany Dokuz Eylul Univ, Sch Med, Dept Psychiat, Konak, Turkey Istanbul Univ, Istanbul Fac Med, Dept Psychiat, Psychot Disorders Res Unit, Istanbul, Turkey Ankara Univ, Sch Med, Dept Psychiat, Cebeci Hosp, TR-06100 Ankara, Turkey Ankara Univ, Brain Res Ctr, TR-06100 Ankara, Turkey Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA Middle E Tech Univ, Dept Psychol, TR-06531 Ankara, Turkey Diskapi YB Res & Training Hosp, Ankara, Turkey Turkish Federat Schizophrenia Assoc, Ankara, Turkey Ataturk Training & Res Hosp, Psychiat Clin, Ankara, Turkey Manisa Mental Hlth Hosp, Manisa, Turkey Istanbul Univ, Expt Med Res Inst, Dept Adv Neurol Sci, Istanbul Fac Med, Istanbul, Turkey Univ Complutense, IiSGM CIBERSAM, Dept Child & Adolescent Psychiat, Hosp Gen Univ Gregorio Maranon,Sch Med, E-28040 Madrid, Spain Univ Barcelona, Dept Psychiat, Hosp Clin, IDIBAPS,Ctr Invest Biomed Red Salud Mental CIBERS, Barcelona, Spain Univ Valencia, Sch Med, Dept Psychiat, Ctr Invest Biomed Red Salud Mental CIBERSAM, Valencia, Spain Univ Oviedo, Sch Med, Dept Med,Psychiat Area, Ctr Invest Biomed Red Salud Mental CIBERSAM, Oviedo, Spain Univ Santiago de Compostela, Dept Mental Hlth & Drug Addit Assistance, Hlth Serv Galicia,Psychiat Genet Grp IDIS, Hosp Clin,Ctr Invest Biomedica Red Salud Mental C, Santiago de Compostela 15706, Spain Hosp Virgen de la Luz, Serv Psiquiat, Dept Psychiat, Cuenca, Spain Hosp Univ Infanta Leonor Hosp Virgen Torre, Villa de Vallecas Mental Hlth Ctr, Villa de Vallecas Mental Hlth Dept, Madrid, Spain Hosp Univ Infanta Leonor Hosp Virgen Torre, Puente de Vallecas Mental Hlth Dept, Ctr Salud Mental Puente Vallecas, Madrid, Spain Hosp Clin Univ, Fdn Publ Galega Med Xenomica, Santiago de Compostela, Spain Univ Complutense, Sch Med, Hosp Gen Univ Gregorio Maranon, Dept Psychiat, E-28040 Madrid, Spain Hosp Psiquiatr Conxo, Santiago de Compostela, Spain Univ Amsterdam, Acad Med Ctr, Early Psychosis Sect, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands Vrije Univ Amsterdam, Dept Clin Psychol, Amsterdam, Netherlands EMGO Inst Hlth & Care Res, Amsterdam, Netherlands Parnassia Psychiat Inst, Dept Psychosis Res, the Hague, Netherlands Rivierduinen Psychiat Inst, Leiden, Netherlands Grp Hosp Mondor, AP HP, Creteil, France Hop Henri Mondor, INSERM, U955, Equipe 15, F-94010 Creteil, France Univ Paris Est, Fac Med, Creteil, France Fdn Fondamental, Creteil, France CMP B CHU, F-63003 Clermont Ferrand 1, France Univ Auvergne, EA 7280, Clermont Ferrand, France EPS Maison Blanche, Paris, France UPC KU Leuven, Dept Neurosci, UPC, Kortenberg, Belgium UPC, Dept Neurosci, Res Grp Psychiat, Leuven, Belgium Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Human Genet, Leuven, Belgium Assoc Sci Res Multiple Births, Ghent, Belgium Univ Ghent, Dept Neurol, Ghent Univ Hosp, B-9000 Ghent, Belgium Univ Athens, Sch Med, Eginit Hosp, Athens 11528, Greece Med Univ Vienna, Dept Psychiat & Psychotherapy, Vienna, Austria Psychiat Univ Clin Basel, Ctr Gender Res & Early Detect, Basel, Switzerland Psychiat Univ Clin Basel, Diagnost & Crisis Intervent Ctr, Basel, Switzerland Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany Univ Hong Kong, Li Ka Shing Fac Med, Ctr Genom Sci, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Li Ka Shing Fac Med, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Queen Mary Hosp, Li Ka Shing Fac Med, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Queen Mary Hosp, Li Ka Shing Fac Med, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China Univ Basque Country, Univ Deusto, Interuniv Chair Law & Human Genome Prov Govt Bisk, Bilbao, Bizkaia, Spain Univ Zaragoza, Zaragoza, Spain Univ Cambridge, Dept Psychiat, Cambridge, England UCL, Div Psychiat, London, England Royal Coll Surgeons Ireland, Beaumont Hosp, Educ & Res Ctr, Dept Psychiat, Dublin 9, Ireland Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, Munich, Germany Univ Bologna, Alma Mater Studiorium, Psychiat Unit, Dept Med & Surg Sci, Bologna, Italy Univ Bologna, Alma Mater Studiorium, Genet Unit, Dept Med & Surg Sci, Bologna, Italy Local Hlth Trust, Dept Mental Hlth & Pathol Addict, Bologna, Italy Univ Palermo, Sect Psychiat, Dept Expt Biomed & Clin Neurosci, Palermo, Italy P Giaccone Gen Hosp, Unit Psychiat, Palermo, Italy Univ Melbourne, Ctr Youth Mental Hlth, Parkville, Vic 3052, Australia Univ Melbourne, Melbourne Neuropsychiat Ctr, Carlton, Vic, Australia Univ São Paulo, Fac Med, Dept Med Prevent, BR-01246903 São Paulo, Brazil Univ São Paulo, Nucleo Pesquina Saude Mental Populac, São Paulo, Brazil Univ São Paulo, Fac Med Ribeirao Preto, Dept Neurociencias & Ciencias Comportamento, BR-14049 Ribeirao Preto, Brazil Univ Verona, Sect Psychiat, Dept Publ Hlth & Community Med, I-37100 Verona, Italy Copenhagen Univ Hosp, Res Unit, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark Univ Paris 05, Fac Med, Serv Hosp Univ, Hop St Anne, Paris, France Univ Autonoma Barcelona, Dept Psicol Clin & Salut, E-08193 Barcelona, Spain St Pere Claver Fundacio Sanitaria, Dept Salut Mental, Barcelona, Spain Univ N Carolina, Dept Psychol, Greensboro, NC 27412 USA CIBERSAM, Spanish Mental Hlth Res Network, Barcelona, Spain Universidade Federal de São Paulo, Dept Psychiat, PRISMA Early Intervent Program, São Paulo, Brazil Univ Belgrade, Sch Med, Beograd, Serbia Universidade Federal de São Paulo, Dept Psychiat, PRISMA Early Intervent Program, São Paulo, Brazil European Community: HEALTH-F2-2009-241909 Web of Science

BackgroundUbiquitous negative emotional states such as depression, anxiety and stress in adulthood are related to individual life scenario, particularly influenced by exposure to environmental risk factors. Here, we investigated if sub-threshold negative emotional states in general population can be predicted by experience of trauma in the childhood.MethodA sample of 106 healthy young adult participants from Belgrade and surroundings (43.4% male, age 29.2 ± 6.6 years, mean IQ 106.4 ± 15.9) fulfilled Childhood Trauma Questionnaire (CTQ) to identify emotional or physical abuse/neglect or sexual abuse. Present level of negative affectivity was measured by Depression Anxiety Stress Scale (DASS). Hierarchical linear regression analysis was conducted to identify subtypes of trauma as predictors of the negative affectivity.ResultsMean CTQ and DASS scores were 31.2 ± 6.7 and 16.4 ± 16.8, respectively. An exposure to given risk factors in the past correlated significantly with intensity of the present negative affective states (r = 0.290, P = 0.004). For the prediction of anxiety, the most important traumatism subtypes were emotional abuse, emotional neglect and physical abuse (P = 0.001; 0.028; and 0.041, respectively). Depressive symptoms were predicted only by the emotional abuse in the past (P = 0.008).ConclusionBased on clinical samples, findings from the literature yielded greater risk for mood and anxiety disorders after exposure to emotional, in comparison to the physical trauma. We confirmed the same pattern of correlations in the healthy subject's sample, who had no history mental disorders. Evaluation of the interaction effects among emotional trauma and genotype is strongly recommended in the identification of subjects at risk and for the prevention.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Introduction: There are different proofs about association of autonomic nervous system dysfunction, especially nonlinear parameters, with higher mortality after myocardial infarction. Objective The objective of the study was to determine predictive value of Poincare plot as nonlinear parameter and other significant standard risk predictors: ejection fraction of the left ventricle, late potentials, ventricular arrhythmias, and QT interval. Method The study included 1081 patients with mean follow up of 28 months (ranging fom 0-80 months). End-point of the study was cardiovascular mortality. The following diagnostic methods were used during the second week: ECG with commercial software Schiller AT-10: short time spectral analysis of RR variability with analysis of Poincare plot as nonlinear parameter and late potentials; 24-hour ambulatory ECG monitoring: QT interval, RR interval, QT/RR slope, ventricular arrhythmias (Lown >II); echocardiography examinations: systolic disorder (defined as EF 350 ms, positive late potentials, systolic dysfunction, Poincare plot as a point, ventricular arrhythmias (Lown > II). In multivariate analysis, the significant risk predictors were: Poincare plot as a point and mean RR interval lower than 800 ms. Conclusion Mean RR interval lower than 800 ms and nonlinear and space presentation of RR interval as a point Poincare plot were multivariate risk predictors.