Search

The EU-GEI Project was funded by grant agreement Health-F2-2010-241909 from the European Community’s Seventh Framework program. The Brazilian study was funded by grant 2012-0417-0 from the São Paulo Research Foundation, D'Andrea, Giuseppe; Lal, Jatin; Tosato, Sarah;Gayer-Anderson, Charlotte;Jongsma, Hannah E.;Stilo, Simona A.; van der Ven, Els;Quattrone, Diego;Velthorst, Eva;Berardi, Domenico;Rossi Menezes, Paulo; Arango, Celso; Parellada, Mara; Lasalvia, Antonio; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Sideli, Lucia; Bobes, Julio; Bernardo, Miguel; Sanjuan, Julio; Santos, Jose Luis; Arrojo, Manuel; Marta Del-Ben, Cristina; Tripoli, Giada; Llorca, Pierre-Michel; de Haan, Lieuwe; Selten, Jean-Paul; Tortelli, Andrea; Szoke, Andrei; Muratori, Roberto; Rutten, Bart P.; van Os, Jim; Jones, Peter B.; Kirkbride, James B.; Murray, Robin M.; di Forti, Marta; Tarricone, Ilaria; Morgan, Craig

AbtractStudies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Adversity scores were created for abuse, neglect and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III) between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null-hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 1.68; p = p < 0.001; neglect: OR = 2.27; p =

Studies conducted in psychotic disorders have shown that DNA-methylation (DNAm) is sensitive to the impact of Childhood Adversity (CA). However, whether it mediates the association between CA and psychosis is yet to be explored. Epigenome-wide association studies (EWAS) using the Illumina Infinium-Methylation EPIC array in peripheral blood tissue from 366 First-episode of psychosis and 517 healthy controls was performed. Polyvictimization scores were created for abuse, neglect, and composite adversity with the Childhood Trauma Questionnaire (CTQ). Regressions examining (I) CTQ scores with psychosis; (II) with DNAm EWAS level and (III), then between DNAm and caseness, adjusted for a variety of confounders were conducted. Divide-Aggregate Composite-null Test for the composite null hypothesis of no mediation effect was conducted. Enrichment analyses were conducted with missMethyl package and the KEGG database. Our results show that CA was associated with psychosis (Composite: OR = 3.09; p =

Schizophrenia is associated with a weighted average of 14.5 years of potential life lost according to a recent meta-analysis. This is partly explained by high rates of suicide and a high prevalence of non-psychiatric comorbidity (cardiovascular diseases, diabetes, cancers…). However, all these causes could not fully explain the loss of life expectancy in people suffering from schizophrenia. Life expectancy has been strongly correlated with telomere length (TL). Telomeres are noncoding structures consisting of DNA TTAGGG tandem repeats and associated proteins located at the end of the chromosomes. Their role is to help preserve genome stability by protecting chromosomal ends from the loss of genetic material. The progressive loss of telomeric material during cell divisions has led researchers to consider telomeres as molecular clocks that measure the number of divisions left until cellular death. The fact that both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy has fueled the interest in the study of TL in schizophrenia. In this article, after a detailed review of the literature on the relationships between telomere length and schizophrenia, we discuss the different pathophysiological mechanisms which might explain this association. Based on this analysis, in the last part of the article we discuss potential research, therapeutic and prevention prospects. To date, the majority of the studies and meta-analyses found a decrease in TL in subjects with schizophrenia compared to control subjects. Conversely, all the studies exploring the TL in subjects suffering from first episode psychosis (FEP) have shown no significant difference from TL in control subjects. This suggests that excessive shortening of telomeres occurs during the course of the disease, thus it seems more probable that schizophrenia (or processes associated with it) affects TL rather than telomere erosion being a cause of the disorder. Several pathophysiological, non-mutually exclusive mechanisms have been proposed to explain the observed data. A first hypothesis to explain the acceleration of the physiological process of telomere erosion in schizophrenia is the activation of inflammation processes and oxidative stress as a consequence of schizophrenia per se. However, it seems more probable that reduced TL may be a result of cumulative exposure to chronic stress related to schizophrenia. Indeed, in healthy individuals a growing body of evidence has linked chronic stress to accelerated shortening of TL. This might explain why telomere erosion is too small to be detected in FEP patients who are younger and have a shorter duration of illness than subjects with schizophrenia. Based on these both explanations, telomere alterations may be considered as a biomarker of illness progression and might be useful for illness staging. Identifying processes associated with TL reduction might improve our understanding of the increased mortality and morbidity in schizophrenia, improve reliability of diagnosis, and hopefully suggest means for prevention and/or treatment. Treatments that prevent exposure and/or vulnerability to stressful life events that ameliorate schizophrenia may also prevent or decelerate telomere erosion. In this perspective, engaging subjects suffering from schizophrenia in a healthy diet and regular activity could be both promising strategies to protect telomere maintenance and improve health span at old age. In addition, the inflammatory process and oxidative stress involved in the physiopathology in at least a subgroup of subjects with schizophrenia could also be responsible for telomere erosion. Thus, an efficient anti-inflammatory therapeutic approach that targets these specific pathways could be of interest in this subgroup to limit telomere erosion. Mindfulness-based stress reduction (MBSR) therapies have been shown to reduce telomere erosion by increasing telomerase activity, although these psychological therapies should be used carefully in psychosis. Finally, advancing our understanding of the relationship between stress, inflammation and TL is of great interest for psychiatric research and for understanding stress effects in this population.

There is growing evidence for a main role of environment in the occurrence of mental disorders such as a psychosocial risk factor, for example, childhood trauma, discrimination linked to minority status, or migrant status. One hypothesis is that social adversity factors influence the risk of schizophrenia through a common pathway: social defeat which could be defined as the impotence of a subject in the face of a situation of social adversity, with a consequential experience of devaluation on the social scale. This review proposes to explain the animal model of social defeat which provides an overview of the neurobiological consequences of chronic stress. Then, we expose this topic in humans, the assessment methods, and its psychopathological field. Finally, we expose epidemiologic and neurobiological evidences, in particular the dopaminergic sensitization process, which provide evidence of a significant role of social defeat in schizophrenia risk due to exposure to psychosocial factors. This etiopathogenic hypothesis has several issues. First, a common pathway to several environmental risk factors could allow an ethiopathogenic model more parcimonious for schizophrenia. It could also allow the assessment and prevention of adversity factors involved in social defeat so as to finally improve the outcome of subjects who have an individual risk for schizophrenia.

This study was funded by the Medical Research Council, the European Community’s Seventh Framework Program grant [agreement HEALTH-F2-2009-241909 (Project EU-GEI)], São Paulo Research Foundation (grant 2012/0417-0), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR BRC at University College London and the Wellcome Trust (grant 101272/Z/12/Z)., Tripoli, G., Quattrone, D., Ferraro, L., Gayer-Anderson, C., Rodriguez, V., La Cascia, C., La Barbera, D., Sartorio, C., Seminerio, F., Tarricone, I., Berardi, D., Szöke, A., Arango, C., Tortelli, A., Llorca, P.-M., De Haan, L., Velthorst, E., Bobes, J., Bernardo, M., Sanjuán, J., Santos, J.L., Arrojo, M., Del-Ben, C.M., Menezes, P.R., Selten, J.-P., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., Lasalvia, A., Tosato, S., Richards, A., O'donovan, M., Rutten, B.P.F., Os, J.V., Morgan, C., Sham, P.C., Murray, R.M., Murray, G.K., Di Forti, M.

Particulate matter with a diameter of less than 10 µm (PM 10 ) or less than 2.5 µm (PM 2.5 ) are major air pollutants poorly studies regarding psychiatric disorders. We aimed to explore the association between PM 10 and PM 2.5 air pollution peaks and the daily number of emergency visits for psychotic and mood disorders. Clinical data were collected from the Emergency department of the Centre Hospitalo-Universitaire Henri-Mondor (Créteil, France) from 2008 to 2018. Air pollution data were collected from public databases. Pollution peaks periods were defined as days for which the daily mean level of PM was above nationally predefined warning thresholds (20 µg/m 3 for PM 2.5 , and 50 µg/m 3 for PM 10 ), and the 6 following days. Multivariable analyses compared the number of daily visits for psychotic and mood disorders according to pollution peak period. After adjustment on meteorological variables, the daily number of emergency visits for psychotic disorders was significantly higher during with PM 2.5 and PM 10 air pollution peaks periods; while the number of visits for unipolar depressive disorders was higher only during PM 10 peaks periods (β=0.059, p-value=0.034). There was no significant differences concerning bipolar disorders. Differences in the effects of PM air pollution on psychotic and mood disorders should be analyzed in further studies.

Particulate matters with a diameter of less than 10 µm (PM

Introduction Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR. Methods We combined data from ten prospective, first-episode psychosis cohorts from across Europe and categorised patients as TR or non-treatment resistant (NTR) after a mean follow up of 4.18 years (s.d. = 3.20) for secondary data analysis. We identified a list of potential predictors from clinical and demographic data recorded at first-episode. These potential predictors were entered in two models: a multivariable logistic regression to identify which were independently associated with TR and a penalised logistic regression, which performed variable selection, to produce a parsimonious prediction model. This model was internally validated using a 5-fold, 50-repeat cross-validation optimism-correction. Results Our sample consisted of N = 2216 participants of which 385 (17 %) developed TR. Younger age of psychosis onset and fewer years in education were independently associated with increased odds of developing TR. The prediction model selected 7 out of 17 variables that, when combined, could quantify the risk of being TR better than chance. These included age of onset, years in education, gender, BMI, relationship status, alcohol use, and positive symptoms. The optimism-corrected area under the curve was 0.59 (accuracy = 64 %, sensitivity = 48 %, and specificity = 76 %). Implications Our findings show that treatment resistance can be predicted, at first-episode of psychosis. Pending a model update and external validation, we demonstrate the potential value of prediction models for TR. Funding: This work was supported by a Stratified Medicine Programme grant to JHM from the Medical Research Council (grant number MR/L011794/1 which funded the research and supported S.E.S., D.A., A.F.P, L.K., R.M.M., D.S., J.T.R.W, & J.H.M.); funding from the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London to D.A. and D.S; and funding from the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) South London at King's College Hospital National Health Service Foundation Trust to S.E.S. The views expressed are those of the author(s) and not necessarily those of the Medical Research Council, National Health Service, the National Institute for Health Research, or the Department of Health. The AESOP (London, UK) cohort was funded by the UK Medical Research Council (Ref: 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 under grant agreement (agreement No.HEALTH-F2-2010–241909, Project EU-GEI). The GAP (London, UK) cohort was funded by the UK National Institute of Health Research(NIHR) Specialist Biomedical Research Centre for Mental Health, South London and Maudsley NHS 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 grant (agreement No. HEALTH-F2-2009-241909, Project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (no. 320030_135736/1 to P.C. and K.Q.D., no 320030-120686, 324730-144064 and 320030-173211 to C.B.E and P.C., and no 171804 to LA); National Center of Competence in Research (NCCR) “SYNAPSY - The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (no 51AU40_125759 to PC and KQD); and Fondation Alamaya (to KQD). The Oslo (Norway) cohort was funded by the Research Council of Norway (#223273/F50, under the Centers of Excellence funding scheme, #300309, #283798) and the South-Eastern Norway Regional Health Authority (#2006233, #2006258, #2011085, #2014102, #2015088 to IM, #2017-112). The Paris (France) cohort was funded by European Community's Seventh Framework Program grant (agreement No. HEALTH-F2-2010–241909, Project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (Grant Number: NU20-04-00393). The Santander (Spain) cohort was funded by the following grants (to B.C.F): Instituto de Salud Carlos III, FIS 00/3095, PI020499, PI050427, PI060507, Plan Nacional de Drogas Research Grant 2005-Orden sco/3246/2004, and SENY Fundatio Research Grant CI 2005-0308007, Fundacion Marques de Valdecilla A/02/07 and API07/011. SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER). The West London (UK) cohort was funded The Wellcome Trust (Grant Number: 042025; 052247; 064607).

BackgroundIn Europe, the incidence of psychotic disorder is high in certain migrant and minority ethnic groups (hence: ‘minorities’). However, it is unknown how the incidence pattern for these groups varies within this continent. Our objective was to compare, across sites in France, Italy, Spain, the UK and the Netherlands, the incidence rates for minorities and the incidence rate ratios (IRRs, minorities v. the local reference population).MethodsThe European Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI) study was conducted between 2010 and 2015. We analyzed data on incident cases of non-organic psychosis (International Classification of Diseases, 10th edition, codes F20–F33) from 13 sites.ResultsThe standardized incidence rates for minorities, combined into one category, varied from 12.2 in Valencia to 82.5 per 100 000 in Paris. These rates were generally high at sites with high rates for the reference population, and low at sites with low rates for the reference population. IRRs for minorities (combined into one category) varied from 0.70 (95% CI 0.32–1.53) in Valencia to 2.47 (95% CI 1.66–3.69) in Paris (test for interaction: p = 0.031). At most sites, IRRs were higher for persons from non-Western countries than for those from Western countries, with the highest IRRs for individuals from sub-Saharan Africa (adjusted IRR = 3.23, 95% CI 2.66–3.93).ConclusionsIncidence rates vary by region of origin, region of destination and their combination. This suggests that they are strongly influenced by the social context.

The influence of psychosocial stressors on psychosis risk has usually been studied in isolation and after the onset of the disorder, potentially ignoring important confounding relationships or the fact that some stressors that may be the consequence of the disorder rather than preexisting. The study of subclinical psychosis could help to address some of these issues. In this study, we investigated whether there was (i) an association between dimensions of subclinical psychosis and several psychosocial stressors including: childhood trauma, self-reported discrimination experiences, low social capital, and stressful life experiences, and (ii) any evidence of environment-environment (ExE) interactions between these factors. Data were drawn from the EUGEI study, in which healthy controls (N = 1497) and siblings of subjects with a psychotic disorder (N = 265) were included in six countries. The association between psychosocial stressors and subclinical psychosis dimensions (positive, negative and depressive dimension as measured by the Community Assessment of Psychic Experiences (CAPE) scale) and possible ExE interactions were assessed using linear regression models. After adjusting for sex, age, ethnicity, country, and control/sibling status, childhood trauma (beta for positive dimension: 0.13, negative: 0.49, depressive: 0.26) and stressful life events (positive: 0.08, negative: 0.16, depressive: 0.17) were associated with the three dimensions. Lower social capital was associated with the negative and depression dimensions (negative: 0.26, depressive: 0.13), and self-reported discrimination experiences with the positive dimension (0.06). Our findings are in favor of independent, cumulative and non-specific influences of social adversities in subclinical psychosis in non-clinical populations, without arguments for E * E interactions. © The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Premorbid functioning and cognitive measures may reflect gradients of developmental impairment across diagnostic categories in psychosis. In this study, we sought to examine the associations of current cognition and premorbid adjustment with symptom dimensions in a large first episode psychosis (FEP) sample. We used data from the international EU-GEI study. Bifactor modelling of the Operational Criteria in Studies of Psychotic Illness (OPCRIT) ratings provided general and specific symptom dimension scores. Premorbid Adjustment Scale estimated premorbid social (PSF) and academic adjustment (PAF), and WAIS-brief version measured IQ. A MANCOVA model examined the relationship between symptom dimensions and PSF, PAF, and IQ, having age, sex, country, self-ascribed ethnicity and frequency of cannabis use as confounders. In 785 patients, better PSF was associated with fewer negative (B=-0.12, 95% C.I. -0.18, -0.06, p

The study of subclinical psychotic manifestations (quantitative schizotypy) represents clinical and public health issues. These manifestations are more common than schizophrenia or depression, but rarely identified while it impacts the quality of life. Screening schizotypy in the general population would make it possible to propose prevention strategies. The objectives of the present research is to better understand the determinants and mechanisms of schizotypy in order to identify population...

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project was funded by grant agreement Health-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework programme., Tarricone, I., D'Andrea, G., Jongsma, H.E., Tosato, S., Gayer-Anderson, C., Stilo, S.A., Suprani, F., Iyegbe, C., Van Der Ven, E., Quattrone, D., Di Forti, M., Velthorst, E., Rossi Menezes, P., Arango, C., Parellada, M., Lasalvia, A., La Cascia, C., Ferraro, L., Bobes, J., Bernardo, M., Sanjuán, I., Santos, J.L., Arrojo, M., Del-Ben, C.M., Tripoli, G., Llorca, P.-M., De Haan, L., Selten, J.-P., Tortelli, A., Szöke, A., Muratori, R., Rutten, B.P., Van Os, J., Jones, P.B., Kirkbride, J.B., Berardi, D., Murray, R.M., Morgan, C.

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project was funded by grant agreement Health-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework programme. The Brazilian study was funded by grant 2012-0417-0 from the São Paulo Research Foundation. Dr Jongsma is funded by the Economic and Social Research Council (grant ES/S011714/1). Dr Kirkbride is funded by the Wellcome Trust and Royal Society (Grant 101272/Z/13/Z). Dr Jongsma and Professor Jones are funded by the National Institute of Health Research Collaboration of Leadership in Applied Health Research and Care East of England. Professor Rutten is funded by the Netherlands Scientific Organisation (VIDI award number 91718336). Dr Jongsma and Dr Kirkbride are supported by the National Institute for Health Research, University College London Hospital, Biomedical Research Centre., Jongsma, H.E., Gayer-Anderson, C., Tarricone, I., Velthorst, E., Van Der Ven, E., Quattrone, D., Di Forti, M., Menezes, P.R., Del-Ben, C.M., Arango, C., Lasalvia, A., Berardi, D., La Cascia, C., Bobes, J., Bernardo, M., Sanjuán, J., Santos, J.L., Arrojo, M., De Haan, L., Tortelli, A., Szöke, A., Murray, R.M., Rutten, B.P., Van Os, J., Morgan, C., Jones, P.B., Kirkbride, J.B.

Treatment-resistant schizophrenia (TRS) affects around 30% of patients with schizophrenia (SZ) resulting in poor functioning, relapses, and reduced quality of life. Convergent findings show that inflammation could contribute to resistance. We thus search for immune signatures of patients with TRS/ultra TRS (UTRS) in a sample of community-dwelling outpatients with SZ. In total, 195 stabilized SZ patients (mean age = 31.2 years, 73% male gender) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. At inclusion, psychotic symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Circulating serum/plasma levels of a large panel of markers reflecting the main inflammatory pathways were evaluated. TRS was defined by current treatment by clozapine (CLZ) and UTRS by current CLZ treatment + PANSS total score ≥ 70. The frequency of TRS and UTRS patients was, respectively, 20% and 7.7% and was defined using multivariable analysis elevated by high levels of interleukin (IL)-12/IL-23p40, IL-17A, IL-10, and beta 2 microglobulin (B2M) and IL-12/IL-23p40, IL-17A, IL-6, IL-10, IFNγ, and B2M, respectively. These observations suggest that resistance and ultra resistance to CLZ treatment are underpinned by pro-inflammatory molecules mainly belonging to the T helper 17 pathway, a finding making sense given the interplay between inflammation and antipsychotic treatment responses. If confirmed, our findings may allow us to consider IL-23/IL-17 pathway as a therapeutic target for patients with resistance to antipsychotics.

Objective To explore the sociodemographic characteristics that might explain the increased incidence of psychosis among immigrants and their descendants in France. Methods Data were collected for all subjects with first contact for psychosis aged between 18 and 64 years, in two catchment areas in the Paris region. Incidence rates (IR) and incidence rate ratios (IRR) were adjusted for gender and age. Results During 805,396 persons‐year at risk, we identified 321 cases of first‐episode psychosis, of which 129 were immigrants and 78 descendants of immigrants. We found that the geographic origin was associated with the risk of psychosis although generation has little impact. Sub‐Saharan African immigrants and their descendants showed the highest risk (IRR = 3.1 and IRR = 2.9, respectively). We observed that living in deprived areas increased the incidence of psychosis (IRR = 1.3, 95CI%: 1.0–1.6), particularly among immigrants (IRR = 1.6; 95% CI: 1.1–2.5). Finally, our study showed that subjects having unstable housing (a proxy for “hard to count population”) could inflate the incidence rates among immigrants. Conclusion The current study shows that the increased risk of psychosis in groups with an immigration background in France is associated with their origin and highlights the importance of socioeconomic factors in modulating this risk., The aim of the present study is to explore the characteristics that might explain this increase: geographic origin, generation (immigrants or their descendants), social environment, and living conditions. We observed that living in deprived areas increased the incidence of psychosis, particularly among immigrants. Geographic origin was associated with the risk of psychosis although generation has little impact and Sub‐Saharan African immigrants and their descendants showed the highest risk.

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme., Aas, M; Alameda, L; Di Forti, M; Quattrone, D; Dazzan, P; Trotta, A; Ferraro, L; Rodriguez, V; Vassos, E; Sham, P; Tripoli, G; La Cascia, C; La Barbera, D; Tarricone, I; Muratori, R; Berardi, D; Lasalvia, A; Tosato, S; Szoke, A; Llorca, PM; Arango, C; Tortelli, A; de Haan, L; Velthorst, E; Bobes, J; Bernardo, M; Sanjuan, J; Santos, JL; Arrojo, M; Del-Ben, CM; Menezes, PR; Selten, JP; Jones, PB; Jongsma, HE; Kirkbride, JB; Rutten, BPF; van Os, J; Gayer-Anderson, C; Murray, RM; Morgan, C

The EU-GEI Project is funded by the European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010–241909 (Project EU-GEI)., Ajnakina, O., Rodriguez, V., Quattrone, D., Di Forti, M., Vassos, E., Arango, C., Berardi, D., Bernardo, M., Bobes, J., De Haan, L., Del-Ben, C.M., Gayer-Anderson, C., Jongsma, H.E., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Rutten, B.P., Santos, J.L., Sanjuán, J., Selten, J.-P., Szöke, A., Tarricone, I., D'andrea, G., Richards, A., Tortelli, A., Velthorst, E., Jones, P.B., Arrojo Romero, M., La Cascia, C., Kirkbride, J.B., Van Os, J., O'donovan, M., Murray, R.M.

International audience; Both shorter telomeres and schizophrenia have been associated with a decrease in life expectancy. Furthermore, several studies found a shorter telomere length (TL) in schizophrenia. Understanding whether or not telomere shortening is directly related to pathophysiology of schizophrenia or is a consequence of a cumulative exposure to chronic stress is of major importance. Comparing the TL of subjects at the very beginning of the disease (FEP) and control subjects could help to decide between these two hypotheses. The aim of the present study was to compare TL between FEP subjects (N=91) and controls (N=137). After accounting for multiple potential confounders, no significant association was observed between FEP and TL. Our result is consistent with the hypothesis that psycho-social stress / adversities and stressful situations in people with schizophrenia affect TL rather than that telomere erosion contributes to the development of this disorder.

International audience; A new etiological model is proposed for schizophrenia that combines variability-enhancing nonspecific factors acting during development with more specific risk factors. This model is better suited than the current etiological models of schizophrenia, based on the risk factors paradigm, for predicting and/or explaining several important findings about schizophrenia: high co-morbidity rates, low specificity of many risk factors, and persistence in the population of the associated genetic polymorphisms. Compared with similar models, e.g., de-canalization, common psychopathology factor, sexual-selection, or differential sensitivity to the environment, this proposal is more general and integrative. Recently developed research methods have proven the existence of genetic and environmental factors that enhance developmental variability. Applying such methods to newly collected or already available data can allow for testing the hypotheses upon which this model is built. If validated, this model may change the understanding of the etiology of schizophrenia, the research models, and preventionbrk paradigms.

Importance: Psychotic disorders contribute significantly to the global disease burden, yet the latest international incidence study of psychotic disorders was conducted in the 1980s. Objectives: To estimate the incidence of psychotic disorders using comparable methods across 17 catchment areas in 6 countries and to examine the variance between catchment areas by putative environmental risk factors. Design, Setting, and Participants: An international multisite incidence study (the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions) was conducted from May 1, 2010, to April 1, 2015, among 2774 individuals from England (2 catchment areas), France (3 catchment areas), Italy (3 catchment areas), the Netherlands (2 catchment areas), Spain (6 catchment areas), and Brazil (1 catchment area) with a first episode of nonorganic psychotic disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes F20-F33) confirmed by the Operational Criteria Checklist. Denominator populations were estimated using official national statistics. Exposures: Age, sex, and racial/ethnic minority status were treated as a priori confounders. Latitude, population density, percentage unemployment, owner-occupied housing, and single-person households were treated as catchment area-level exposures. Main Outcomes and Measures: Incidence of nonorganic psychotic disorders (ICD-10 codes F20-F33), nonaffective psychoses (ICD-10 codes F20-F29), and affective psychoses (ICD-10 codes F30-F33) confirmed by the Operational Criteria Checklist. Results: A total of 2774 patients (1196 women and 1578 men; median age, 30.5 years [interquartile range, 23.0-41.0 years]) with incident cases of psychotic disorders were identified during 12.9 million person-years at risk (crude incidence, 21.4 per 100 000 person-years; 95% CI, 19.4-23.4 per 100 000 person-years). A total of 2183 patients (78.7%) had nonaffective psychotic disorders. After direct standardization for age, sex, and racial/ethnic minority status, an 8-fold variation was seen in the incidence of all psychotic disorders, from 6.0 (95% CI, 3.5-8.6) per 100 000 person-years in Santiago, Spain, to 46.1 (95% CI, 37.3-55.0) per 100 000 person-years in Paris, France. Rates were elevated in racial/ethnic minority groups (incidence rate ratio, 1.6; 95% CI, 1.5-1.7), were highest for men 18 to 24 years of age, and were lower in catchment areas with more owner-occupied homes (incidence rate ratio, 0.8; 95% CI, 0.7-0.8). Similar patterns were observed for nonaffective psychoses; a lower incidence of affective psychoses was associated with higher area-level unemployment (incidence rate ratio, 0.3; 95% CI, 0.2-0.5). Conclusions and Relevance: This study confirmed marked heterogeneity in risk for psychotic disorders by person and place, including higher rates in younger men, racial/ethnic minorities, and areas characterized by a lower percentage of owner-occupied houses., The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework Programme. The Brazilian study was funded by grant 2012/0417-0 from the São Paulo Research Foundation. Dr Kirkbride is funded by the Wellcome Trust and grant 101272/Z/13/Z from the Royal Society. Ms Jongsma and Dr Jones are funded by the National Institute of Health Research Collaboration of Leadership in Applied Health Research and Care East of England.

The search for the genetic factors underlying complex neuropsychiatric disorders has proceeded apace in the past decade. Despite some advances in identifying genetic variants associated with psychiatric disorders, most variants have small individual contributions to risk. By contrast, disease risk increase appears to be less subtle for disease-predisposing environmental insults. In this study, we sought to identify associations between environmental pollution and risk of neuropsychiatric disorders. We present exploratory analyses of 2 independent, very large datasets: 151 million unique individuals, represented in a United States insurance claims dataset, and 1.4 million unique individuals documented in Danish national treatment registers. Environmental Protection Agency (EPA) county-level environmental quality indices (EQIs) in the US and individual-level exposure to air pollution in Denmark were used to assess the association between pollution exposure and the risk of neuropsychiatric disorders. These results show that air pollution is significantly associated with increased risk of psychiatric disorders. We hypothesize that pollutants affect the human brain via neuroinflammatory pathways that have also been shown to cause depression-like phenotypes in animal studies., Exploratory analyses of two independent datasets comprising 151 million Americans and 1.4 million Danes revealed that polluted air was associated with a significantly increased risk of psychiatric disorders, including bipolar disorder and schizophrenia.

International audience; Objectives: We assessed the effect of invalid responding on factor structure and on scores of schizotypy through the factor analysis of the Schizotypal Personality Questionnaire-Brief (SPQ-B) in a sample of 580 Romanian students using 3 validity items and 5 social desirability items.Methods: We examined the factor structure of the SPQ-B, we compared the mean SPQ-B scores between reliable and unreliable responders and between high vs. low social desirability responders, and we re-run the factor analysis restricting the sample to the reliable or low social desirability responders.Results: Factor analysis resulted in a 3-factor solution: Cognitive-perceptual, Interpersonal and Disorganized dimensions. Unreliable responders had lower scores of positive, negative and total schizotypy. Subjects with high social desirability scores had lower scores of disorganized schizotypy. Factor analyses in the samples of "good" responders showed minor differences in reliable responders, whereas, after taking into account the effect of social desirability, 2 items correctly loaded on expected dimensions.Conclusions: Random responding and social desirability could influence scores of schizotypy and factor structure. Simple methods could be used to identify invalid responses. The effect of social desirability could be linked to the phrasing of items.

International audience; Background: Impaired Quality of life (QoL) in schizophrenia has been mostly associated with psychotic and mood symptomatology, insight and functioning so far. Aims: QoL levels remain unsatisfactory due to other factors we aim to explore. Method: We have explored sleep quality with the Pittsburgh Sleep Quality Index, hostility with the Buss&Perry questionnaire, major depression with the Positive and Negative Syndrome Scale depressive factor, functioning with the Global Assessment of Functioning scale and weight gain with body mass index in addition to other classical QoL-associated factors. Results: 559 patients (mean age=31 (SD 9) years, 74% male sex) were included in the national FACE-SZ cohort. Impaired QoL has been significantly associated with respectively major depression, impaired sleep quality, increased hostility, impaired functioning and impaired insight independently of age, sex, treatments, tobacco smoking and body mass index. Major depression was associated with impaired psychological and physical well-being, and impaired self-esteem. Impaired sleep quality has been associated with impaired psychological and physical well-being and sentimental life. Hostility has been associated with impaired psychological well-being and self-esteem, impaired friends’ relationships and impaired autonomy. Weight was associated with impaired physical well-being. Tobacco smoking was associated with higher level of friends’ relationships. Conclusions: Major depression, sleep, hostility, and weight gain have been identified as potential targets to improve QoL in schizophrenia and should be implemented in the recommendations for good practice to optimize schizophrenia care.

Cet article aborde les déterminants des troubles psychotiques à travers l’étude des manifestations psychotiques « atténuées » (ou schizotypie quantitative) ; manifestations plus fréquentes que les troubles constitués (telle que la schizophrénie) mais rarement identifiés et pris en charge alors qu’ils impactent la qualité de vie. Si les déterminants individuels de ces troubles « atténués » sont plutôt bien connus, l’impact des déterminants contextuels (caractéristiques sociales, urbanistiques) des lieux de vie sur leur présence ou leur intensité n’a, par contre, pas encore été étudié. Les relations entre contexte de résidence et schizophrénie ont, en revanche, fait l’objet de recherches spécifiques. A partir de données recueillies auprès de 255 adultes résidant dans trois quartiers de la commune de Créteil, cette étude s’intéresse aux relations entre les représentations (dont l’étendue) du quartier de résidence, les caractéristiques (socio-démographiques et urbanistiques) du quartier et les scores de schizotypie. The study of subclinical psychotic manifestations (quantitative schizotypy) represents clinical and public health issues. These manifestations are more common than schizophrenia or depression, but rarely identified while it impacts the quality of life. Screening schizotypy in the general population would make it possible to propose prevention strategies. The objectives of the present research is to better understand the determinants and mechanisms of schizotypy in order to identify population at risk and hopefully be able to improve prevention and care. The hypothesis is that schizotypy is influenced both by individual and contextual characteristics (social, built). Based on data collected during a survey in the city of Créteil, the aims of this article were to explore the relationships between representations (including size), socioeconomic and urban planning characteristics of the neighborhood of residence and schizotypy scores. In addition, a methodological contribution of this article is to measure and characterize self-defined neighborhoods.

International audience

BackgroundDiagnostic categories within the psychosis spectrum are widely used in clinical practice, however psychosis may occur on a continuum. Therefore, we explored whether the continuous distribution of psychotic symptoms across categories is a function of genetic as well as environmental risk factors, such as polygenic risk scores (PRSs) and cannabis use.MethodsAs part of the EU-GEI study, we genotyped first episode psychosis patients (FEP) and population controls, for whom transdiagnostic dimensions of psychotic symptoms or experiences were generated using item response bi-factor modelling. Linear regression was used, separately in patients and controls, to test the associations between these dimensions and schizophrenia (SZ) PRSs, as well as the combined effect of SZ-PRS and cannabis use on the positive symptom/experience dimensions.ResultsSZ-PRS was associated with negative (B=0.18; 95%CI 0.03 to 0.34) and positive (B=0.19; 95%CI 0.03 to 0.36) symptom dimensions in 617 FEP, and with all the psychotic experience dimensions in 979 controls. The putative effect of SZ-PRS on either symptom or experience dimensions was of a small magnitude. Cannabis use was additionally associated with the positive dimensions both in FEP (B=0.31; 95%CI 0.11 to 0.52) and in controls (B=0.26; 95%CI 0.06 to 0.46), independently from SZ-PRS.ConclusionsWe report two validators to the latent dimensional structure of psychosis. SZ risk variants and cannabis use independently map onto specific dimensions, contributing to variation across the psychosis continuum. Findings support the hypothesis that psychotic experiences have similar biological substrates as clinical disorders.

Background: Some recent studies have challenged the direction of causality for the association between cannabis use and psychotic disorder, suggesting that cannabis use initiation is explained by common genetic variants associated with risk of schizophrenia. We used data from the European Union Gene-Environment Interaction consortium (EUGEI) case-control study to test for the independent and combined effect of heavy cannabis use, and of Schizophrenia Polygenic risk score (SZ PRS), on risk for psychotic disorder. Methods: Genome-wide data were obtained from 492 first episode psychosis patients (FEPp) and from 787 controls of European Ancestry, and used to generate SZ PRS from the summary results of an independent meta-analysis. Information on pattern of cannabis use was used to build a 7-level frequency-type composite cannabis use measure that we previously found was a strong predictor of psychotic disorder. Results: SZ PRS did not predict cannabis initiation (b=0.027; p=0.51) or how frequently controls (b=0.027; p=0.06) or FEPp (b=0.006; p=0.91) used it, or the type of cannabis they used (Controls: b = 0.032; p=0.31); FEPp: b= 0.005; p=0.89). The frequency-type composite cannabis use measure (OR=1.32; 95% CI 1.22-1.44) and SZ PRS (OR=2.29; 95%CI 1.71-3.05) showed independent effects from each other on the OR for psychotic disorder. Conclusion: SZ PRS does not predict an individual s propensity to try cannabis, frequency of use, or the potency of the cannabis used. Our findings provide the first evidence that SZ PRS and heavy cannabis use exert effects independent from each other on the risk for psychotic disorder.

Objective: Individuals with psychotic symptoms may actually correspond to various subgroups, characterized by different patterns of psychotic symptoms as well as specific sociodemographic and clinical correlates. We aimed to identify groups of individuals from the general population with specific patterns of psychotic symptoms. Methods: In a 38,694-subject survey, a latent class analysis was performed to identify subgroups based on the distribution of seven psychotic symptoms taken from the Mini International Neuropsychiatric Interview. The different classes were subsequently compared according to sociodemographic and clinical correlates. Results: The best fit was obtained with a four-class solution, including the following: (1) a class with a low prevalence of all psychotic symptoms (‘LOW’, 85.9%); (2) a class with a high prevalence of all psychotic symptoms (‘HAL + DEL’, 1.7%); and classes with a high prevalence of (3) hallucinations (‘HAL’, 4.5%) or (4) delusions (‘DEL’, 7.9%). The HAL + DEL class displayed higher rates of history of trauma, social deprivation and migrant status, while the HAL and DEL classes displayed intermediate rates between HAL + DEL and LOW. HAL + DEL displayed the highest rates of psychotic and non-psychotic disorders and the use of mental health treatment, while HAL and DEL displayed intermediate rates of these disorders between HAL + DEL and LOW. In comparison to the HAL class, psychotic and substance use disorders were more frequent in the DEL class, while anxiety and mood disorders were less frequent. Conclusion: These findings support the hypothesis of a continuum model relating the level of psychotic symptoms to the level of global psychopathology.

Resume L’objectif de notre etude etait d’analyser la structure factorielle de la version breve du Questionnaire de Personnalite Schizotypique (SPQ-B) dans un format Likert. Une analyse en composante principale de la version francaise de l’echelle a ete realisee dans un echantillon representatif de la population generale ( n = 233). La consistance interne et l’influence de l’âge et du sexe sur le score total et les sous-scores dimensionnels ont egalement ete etudiees. L’echantillon etait constitue de 131 femmes et de 102 hommes avec un âge moyen de 52,7 ± 18,1 ans et un score moyen du SPQ-B de 43,6 ± 13. L’analyse factorielle a montre une solution a 3 facteurs expliquant 47,7 % de la variance, avec un facteur « desorganisation » incluant les items du « comportement bizarre », du « discours bizarre » et de « l’anxiete sociale », un facteur « interpersonnel » incluant les items de la dimension negative et de la « mefiance », et un facteur « cognitif-perceptif » incluant les principaux items de la dimension positive. La consistance interne (coefficient α de Cronbach) pour les 3 sous-echelles et pour le score total etait respectivement de 0,81, 0,81, 0,77 et 0,88. Nous n’avons pas retrouve d’influence de l’âge et du sexe sur les differents scores de schizotypie. Notre etude confirme la structure tridimensionnelle de la schizotypie et montre que la version francaise du SPQ-B format Likert presente de bonnes qualites psychometriques. Cet outil apparait comme un instrument fiable et facile d’utilisation pour mesurer l’intensite des traits schizotypiques en population non malade.

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant inSNAP25,rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combinedin vitroandin vivoapproaches in humans to understand the functional impact of the at-risk allele. Thus, we showedin vitrothat thers6039769C allele was sufficient to increase theSNAP25transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that theSNAP25b/SNAP25aratio was increased in schizophrenic patients carrying thers6039769at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala–ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation ofSNAP25on modulating the development and plasticity of the prefrontal–limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENTFunctional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation ofSNAP25on modulating the development and plasticity of the prefrontal–limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

International audience

BackgroundThe “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.Methods817 FEP patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC (assessed by the number of beads drawn on the probabilistic reasoning “beads” task) and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.ResultsThe estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia Polygenic Risk Score (SZ PRS) 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 to 0.76, pp=0.006), but did not relate to delusions in patients.Conclusionsthe JTC reasoning bias in psychosis is not a specific cognitive deficit but is rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to psychotic-like experiences, independent of IQ. The work has potential to inform interventions targeting cognitive biases in early psychosis.

Background Sexual dysfunctions (SD) are frequent in schizophrenia (SZ) and associated with treatment withdrawal, however they remain under-explored and under-treated. To date, most of the studies have focused on SD as antipsychotics' side effects in therapeutic trials. Aims The objectives of the present study were to determine the SD prevalence in stabilized SZ outpatients and their clinical, pharmacological and biological correlates. Method Two hundred and thirty-seven participants (61.2% men) were consecutively included and received a thorough 2 days- clinical assessment including the self-reported Sexual Functioning Questionnaire (SFQ). SD was defined by a SFQ score ≥ 8. Results Two hundred and thirty-seven subjects were recruited in the FACE-SZ cohort, 41% of them reported sexual dysfunctions. In multivariate analyses, SD have been associated with current major depressive disorder (adjusted odd ratio aOR = 2.29[1.08–4.85], p = .03), anticholinergic prescription (aOR = 2.65, p = .02) and chronic low-grade inflammation (aOR = 2.09, p = .03) independently of age, gender, current cannabis use disorder and olanzapine prescription. No antipsychotic has been associated with increased or decreased SD rate. Conclusions SD are frequent in SZ subjects. Major depression, anticholinergic prescription and chronic low-grade peripheral inflammation may be the three targets of interest for addressing this specific issue.

Background Several have suggested a link between discrimination phenomena and psychotic disorders. Since this is a potentially modifiable factor, it seems important to clarify the links between discrimination and psychotic disorders. In the hypothesis of the psychotic continuum, schizotypal features in the general population are intermediate phenotypes in schizophrenia studies. In this study, the aim was to study the links between discrimination and level of schizotypy in the general population. We assumed that exposure to discrimination experiences is associated with increased levels of schizotypy. Methods Subjects from the general population (N = 1456), without psychotic disorders, were recruited in 17 cities and 6 countries (Brazil, Spain, France, Holland, Italy, UK). Each subject completed the Community Assessment of Psychic Experiences (CAPE), a autoquestionaire considered to assess the level of psychometric schizotypy (with positive, negative and depressive dimensions) and the 20-item Perceived Discrimination Scale developed by Williams et al. Linear regression analyzes were used with discrimination as an explanatory variable and CAPE scores as variables to be explained. Results We show that an increase in the perceived discrimination score was associated with significantly higher levels of schizotypy, in the positive (p = 1.7.10-10), negative (p = 3.4.10-10) and the depressed dimensions (p = 2.1.10-10). In more than half of the subjects who reported discrimination experiences, the reason for the discrimination invoked was not one of the reasons given. Ethnicity remains, however, a major cause of reported discrimination. Discussion The stress-vulnerability model could explain the link between discrimination and schizotypy, though dysregulation of the hypothalamo-pituitary axis and cortisol secretion in subjects with schizotypy, preventing them from responding adaptively to social stress. Psychological and social factors also seem to play a role in stress management.

Objectives Incidence-prevalence-mortality (IPM) models have been developped to estimate incidence or prevalence when one of these two measures is unavailable. We aimed to test the consistency of an IPM model of psychotic disorders on a recent incidence-prevalence couple dataset and to identify potential causes of inconsistency by applying the model to (a) the whole population, (b) female and male subgroups, (c) migrant subgroups, and (d) psychotic disorders with age at onset (AAO) between 18 and 24 (18-24 AAO). Methods We modelled prevalence (MP) using incidence data and the expected mortality and remission values. We then compared the MP to the observed prevalence (OP). Results In the whole population, the model significantly underestimated the prevalence (MP = 3.30, 95% CI [2.97, 3.66]; OP = 4.98, 95% CI [4.58, 5.41]). The results were similar for the two genders. In the migrants group, results were in the opposite direction, the model significantly overestimating the prevalence. Finally, in the 18-24 AAO subgroup, the model performed well, with OP and MP not significantly different. Conclusion These results suggest that standard IPM models do not perform well for psychotic disorders and more complex models taking into account the heterogeneity of the sample (in terms of remission, mortality, population movements, etc.) need to be developed.

Current medical research has focused on diseases and their associated risk factors. As such, these factors are assumed to have a deleterious effect. An alternative hypothesis is that some of these risk factors would also increase the chance for an opposite, positive outcome. To test this hypothesis, we considered exceptional social achievement and schizophrenia as opposite outcomes. Sixty years ago, researchers in France collected data on socio-demographic factors associated with exceptional social achievement. As the number of female subjects in the original database was very limited, we restricted our analyses to men. We tested the odds of achieving prominence in the presence of factors known to be associated with an increased risk of schizophrenia, namely migration, urbanicity, seasonality of birth, birth order, and paternal age. Three of the five factors tested significantly increased the odds for exceptional social achievement (urban birth, being the first-born and father’s age over 35). Our findings suggest that some of the factors that are currently considered as risk factors for schizophrenia could diversifying factors. Widening the focus of research to include all potential effects of factors associated with disease could have important consequences on our understanding of causal mechanisms and for designing public health interventions.

Background The synaptosomal associated protein SNAP25 is crucial for synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions. We recently identified a promoter variant in SNAP25, rs6039769, associated with bipolar disorder and gene expression in prefrontal cortex. Methods Here, we performed a genetic association study using this variation on two independent cohorts of 288 and 173 subjects with schizophrenia and 315 unaffected control individuals. We replicated our results using data from the schizophrenia group of the Psychiatric Genomics Consortium (PGC). Functional consequences combined both in vitro and post-mortem gene expression analysis on 30 patients with schizophrenia and 33 unaffected controls. Structural and functional magnetic resonance imaging in regards to SNAP25 genotypes was performed on 71 subjects and replicated on 121 individuals. Results We showed that rs6039769 was associated with schizophrenia in the two cohorts of patients as well as in the Caucasian population of the PGC cohort and demonstrated in vitro this variant was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis, we showed that the SNAP25b:SNAP25a ratio was increased in patients carrying the at-risk allele. Imaging genetics studies revealed that risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala. Discussion This multi-level functional study brings strong evidence for the functional consequences of this SNAP25 variation on the prefrontal-limbic network and the increased risk of developing associated psychiatric disorders.

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala–ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal–limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia. SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal–limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

Despite significant progresses in our knowledge of the risk factors for schizophrenia, we still are several steps short of implementing effective prevention strategies. Universal prevention strategies have several theoretical advantages but their implementation has been limited to date by their costs and lack of methods to assess their efficiency. To overcome this limitation, we suggest, based on research from therapeutic trials at individual level, the use of surrogate endpoints (SEs) at population level. We further suggest that subclinical measures of psychosis at population level are good SEs candidates for assessing universal measures for schizophrenia prevention.

International audience; AbstractBACKGROUND:We aimed to explore the sociodemographic and psychiatric correlates of psychotic symptoms in a large general population sample.METHODS:The French Mental Health in the General Population cross-sectional survey interviewed 38,694 individuals using the Mini International Neuropsychiatric Interview. We looked for associations between the presence of lifetime psychotic symptoms, sociodemographic characteristics (including migrant status over three generations) and clinical characteristics. We then looked for associations regarding only hallucinations, delusional symptoms, and the co-occurrence of both hallucinations and delusional symptoms. To test the psychosis continuum hypothesis, associations with sociodemographic characteristics were compared with the characterized psychotic disorders' associations.RESULTS:We found that 22.3% of the population declared psychotic symptoms without psychotic disorders, including 5.7% who declared hallucinations, 20.5% delusional symptoms, 4.0% both hallucinations and delusional symptoms, and 2.8% characterized psychotic disorders. The presence of psychotic symptoms was associated with young age, migrant status (over three generations), secondary education level, low-income level and never-married and separated marital status. Hallucinations, delusional symptoms and the co-occurrence of both hallucinations and delusional symptoms showed the same correlates, and hallucinations were also associated with elementary education level. Characterized psychotic disorders showed the same correlates. Concerning clinical outcomes, the presence of psychotic symptoms, hallucinations and delusional symptoms was associated with all non-psychotic disorders, i.e., bipolar, depressive, alcohol use, generalized anxiety, social phobia, panic and post-traumatic stress disorders and dysthymia (except dysthymia, which was not associated with hallucinations).CONCLUSIONS:Our results indicate that psychotic symptoms are associated with broad psychopathologies and support the continuum model of psychosis.