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IMPORTANCE Although hypothesis-driven research has identified several factors associated with psychosis, this one-exposure-to-one-outcome approach fails to embrace the multiplicity of exposures. Systematic approaches, similar to agnostic genome-wide analyses, are needed to identify genuine signals.OBJECTIVE To systematically investigate nongenetic correlates of psychotic experiences through data-driven agnostic analyses and genetically informed approaches to evaluate associations.DESIGN, SETTING, PARTICIPANTS This cohort study analyzed data from the UK Biobank Mental Health Survey from January 1 to June 1, 2021. An exposome-wide association study was performed in 2 equal-sized split discovery and replication data sets. Variables associated with psychotic experiences in the exposome-wide analysis were tested in a multivariable model. For the variables associated with psychotic experiences in the final multivariable model, the single-nucleotide variant-based heritability and genetic overlap with psychotic experiences using linkage disequilibrium score regression were estimated, and mendelian randomization (MR) approaches were applied to test potential causality. The significant associations observed in 1-sample MR analyses were further tested in multiple sensitivity tests, including collider-correction MR, 2-sample MR, and multivariable MR analyses.EXPOSURES After quality control based on a priori criteria, 247 environmental, lifestyle, behavioral, and economic variables.MAIN OUTCOMES AND MEASURES Psychotic experiences.RESULTS The study included 155 247 participants (87 896 [57%) female; mean [SD] age, 55.94 [7.74] years). In the discovery data set, 162 variables (66%) were associated with psychotic experiences. Of these, 148 (91%) were replicated. The multivariable analysis identified 36 variables that were associated with psychotic experiences. Of these, 28 had significant genetic overlap with psychotic experiences. One-sample MR analyses revealed forward associations with 3 variables and reverse associations with 3. Forward associations with ever having experienced sexual assault and pleiotropy of risk-taking behavior and reverse associations without pleiotropy of experiencing a physically violent crime as well as cannabis use and the reverse association with pleiotropy of worrying too long after embarrassment were confirmed in sensitivity tests. Thus, associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables. For several variables, the direction of the association was reversed in the final multivariable and MR analyses.CONCLUSIONS AND RELEVANCE The findings of this study underscore the need for systematic approaches and triangulation of evidence to build a knowledge base from ever-growing observational data to guide population-level prevention strategies for psychosis.

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ_PRS), bipolar disorder (BD_PRS), major depression (MD_PRS), and IQ (IQ_PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean_IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean_IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ_PRS than controls [F(4,1319) = 20.4, P

Parents are known to provide a lasting basis for their children's social development. Understanding parent-driven socialization is particularly relevant in adolescence, as an increasing social independence is developed. However, the relationship between key parenting styles of care and control and the microlevel expression of daily-life social interactions has been insufficiently studied. Adolescent and young adult twins and their nontwin siblings (N = 635; mean age = 16.6; age range = 14.2-21.9; 58.6% female; 79.5% in or having completed higher secondary/tertiary education; 2.8% speaking language other than Dutch at home) completed the Parental Bonding Instrument (PBI) on parental care and control. Participants also completed a 6-day experience sampling period (10 daily beeps, mean compliance = 68.0%) to assess daily-life social interactions. Higher overall parental bonding quality (of both parents) related to more positive social experiences in daily life (e.g., belonging in company), but not to more social behaviors (e.g., being with others). Factor analysis indicated a three-factor structure of the PBI, with care, denial of psychological autonomy, and encouragement of behavioral freedom. Paternal care was uniquely predictive of better social experiences. These findings demonstrate how parenting styles may be uniquely associated with how adolescents experience their social world, with a potentially important role for fathers in particular. This complements the long-held idea of socialization through parenting by bringing it into the context of daily life and implies how both conceptualizations of social functioning and interventions aimed at alleviating social dysfunction might benefit from a stronger consideration of day-to-day social experiences. (PsycInfo Database Record (c) 2022 APA, all rights reserved). ispartof: DEVELOPMENTAL PSYCHOLOGY vol:58 issue:4 pages:792-805 ispartof: location:United States status: published

The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EUGEI); The Spanish sample was supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024) (...), Velthorst, E., Mollon, J., Murray, R.M., de Haan, L., Germeys, I.M., Glahn, D.C., Arango, C., van der Ven, E., Di Forti, M., Bernardo, M., Guloksuz, S., Delespaul, P., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Santos, J.L., Jiménez-López, E., Sanjuan, J., Aguilar, E.J., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Atbaşoğlu, C., Saka, M.C., Üçok, A., Alptekin, K., Akdede, B., Binbay, T., Altınyazar, V., Ulaş, H., Yalınçetin, B., Gümüş-Akay, G., Beyaz, B.C., Soygür, H., Cankurtaran, E.Ş., Kaymak, S.U., Maric, N.P., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Del-Ben, C.M., Ferraro, L., Gayer-Anderson, C., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., La Cascia, C., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Morgan, C., Quattrone, D., Menchetti, M., Selten, J.-P., Szöke, A., Tarricone, I., Tortelli, A., McGuire, P., Valmaggia, L., Kempton, M.J., van der Gaag, M., Riecher-Rössler, A., Bressan, R.A., Barrantes-Vidal, N., Nelson, B., McGorry, P., Pantelis, C., Krebs, M.-O., Ruhrmann, S., Sachs, G., Rutten, B.P.F., van Os, J., Alizadeh, B.Z., van Amelsvoort, T., Bartels-Velthuis, A.A., Bruggeman, R., van Beveren, N.J., Luykx, J.J., Cahn, W., Simons, C.J.P., Kahn, R.S., Schirmbeck, F., van Winkel, R., Calem, M., Tognin, S., Modinos, G., Pisani, S., Kraan, T.C., van Dam, D.S., Burger, N., Amminger, G.P., Politis, A., Goodall, J., Borgwardt, S., Studerus, E., Gadelha, A., Brietzke, E., Asevedo, G., Asevedo, E., Zugman, A., Domínguez-Martínez, T., Monsonet, M., Cristóbal-Narváez, P., Racioppi, A., Kwapil, T.R., Kazes, M., Daban, C., Bourgin, J., Gay, O., Mam-Lam-Fook, C., Nordholm, D., Rander, L., Krakauer, K., Glenthøj, L.B., Glenthøj, B., Gebhard, D., Arnhold, J., Klosterkötter, J., Lasser, I., Winklbaur, B., Reichenberg, A., EU-GEI High Risk Study

Background Adverse childhood experiences (ACE) can affect educational attainments, but little is known about their impact on educational achievements in people at clinical high risk of psychosis (CHR). Methods In total, 344 CHR individuals and 67 healthy controls (HC) were recruited as part of the European Community’s Seventh Framework Programme-funded multicenter study the European Network of National Schizophrenia Networks Studying Gene–Environment Interactions (EU-GEI). The brief version of the Child Trauma Questionnaire was used to measure ACE, while educational attainments were assessed using a semi-structured interview. Results At baseline, compared with HC, the CHR group spent less time in education and had higher rates of ACE, lower rates of employment, and lower estimated intelligence quotient (IQ). Across both groups, the total number of ACE was associated with fewer days in education and lower level of education. Emotional abuse was associated with fewer days in education in HC. Emotional neglect was associated with a lower level of education in CHR, while sexual abuse was associated with a lower level of education in HC. In the CHR group, the total number of ACE, physical abuse, and neglect was significantly associated with unemployment, while emotional neglect was associated with employment. Conclusions ACE are strongly associated with developmental outcomes such as educational achievement. Early intervention for psychosis programs should aim at integrating specific interventions to support young CHR people in their educational and vocational recovery. More generally, public health and social interventions focused on the prevention of ACE (or reduce their impact if ACE occur) are recommended.

BACKGROUND: Ethnic minorities in the Netherlands face an excess psychosis risk, and understanding of causality remains limited. Linguistic disadvantage and other indicators of societal exclusion might play a role, and offer potential targets for public health interventions.AIM: To establish the contribution of linguistic disadvantage, indicators of social distance and perceived discrimination to the increased risk of psychoses in migrants and ethnic minorities.METHODS: We used the Dutch data from an international case-control study into psychotic disorders (the EU-GEI study). A first episode of psychosis was our outcome variable, and we used well-defined data on established confounders (e.g. age and sex) and indicators of ethnicity, social distance, linguistic disadvantage and perceived discrimination as our predictor variables.RESULTS: Ethnic minorities face an increased psychosis risk. This appears to be the case for both first- and second- generation migrants and so-called ‘Western’ and non-Western migrants. Though confounders and social distance appear to contribute, linguistic disadvantage appears to play a role in the excess psychosis risk in first-generation migrants.CONCLUSION: Reducing the social consequences of linguistic disadvantage or social distance might be a starting point for concrete public health interventions aimed at preventing the increased psychosis risk faced by first-generation migrants.

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10−3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10−4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10−3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10−7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.