Gene-environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding.

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene-environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism.

Association of preceding psychosis risk states and non-psychotic mental disorders with incidence of clinical psychosis in the general population: a prospective study in the NEMESIS-2 cohort.

The validity and clinical utility of the concept of "clinical high risk" (CHR) for psychosis have so far been investigated only in risk-enriched samples in clinical settings. In this population-based prospective study, we aimed - for the first time - to assess the incidence rate of clinical psychosis and es-timate the population attributable fraction (PAF) of that incidence for preceding psychosis risk states and DSM-IV diagnoses of non-psychotic mental disorders (mood disorders, anxiety disorders, alcohol use disorders, and drug use disorders). All analyses were adjusted for age, gender and education. The incidence rate of clinical psychosis was 63.0 per 100,000 person-years. The mutually-adjusted Cox proportional hazards model indicated that preceding diagnoses of mood disorders (hazard ratio, HR=10.67, 95% CI: 3.12-36.49), psychosis high-risk state (HR=7.86, 95% CI: 2.76-22.42) and drug use disorders (HR=5.33, 95% CI: 1.61-17.64) were associated with an increased risk for clinical psychosis incidence. Of the clinical psychosis incidence in the population, 85.5% (95% CI: 64.6-94.1) was attributable to prior psychopathology, with mood disorders (PAF=66.2, 95% CI: 33.4-82.9), psychosis high-risk state (PAF=36.9, 95% CI: 11.3-55.1), and drug use disorders (PAF=18.7, 95% CI: -0.9 to 34.6) as the most important factors. Although the psychosis high-risk state displayed a high relative risk for clinical psychosis outcome even after adjusting for other psychopathology, the PAF was comparatively low, given the low prevalence of psychosis high-risk states in the population. These findings provide empirical evidence for the "prevention paradox" of targeted CHR early intervention. A comprehensive prevention strategy with a focus on broader psychopathology may be more effective than the current psychosis-focused approach for achieving population-based improvements in prevention of psychotic disorders.

The Complexities of Evaluating the Exposome in Psychiatry: A Data-Driven Illustration of Challenges and Some Propositions for Amendments.

Identifying modifiable factors through environmental research may improve mental health outcomes. However, several challenges need to be addressed to optimize the chances of success. By analyzing the Netherlands Mental Health Survey and Incidence Study-2 data, we provide a data-driven illustration of how closely connected the exposures and the mental health outcomes are and how model and variable specifications produce "vibration of effects" (variation of results under multiple different model specifications). Interdependence of exposures is the rule rather than the exception. Therefore, exposure-wide systematic approaches are needed to separate genuine strong signals from selective reporting and dissect sources of heterogeneity. Pre-registration of protocols and analytical plans is still uncommon in environmental research. Different studies often present very different models, including different variables, despite examining the same outcome, even if consistent sets of variables and definitions are available. For datasets that are already collected (and often already analyzed), the exploratory nature of the work should be disclosed. Exploratory analysis should be separated from prospective confirmatory research with truly pre-specified analysis plans. In the era of big-data, where very low P values for trivial effects are detected, several safeguards may be considered to improve inferences, eg, lowering P-value thresholds, prioritizing effect sizes over significance, analyzing pre-specified falsification endpoints, and embracing alternative approaches like false discovery rates and Bayesian methods. Any claims for causality should be cautious and preferably avoided, until intervention effects have been validated. We hope the propositions for amendments presented here may help with meeting these pressing challenges.

p16 INK4A overexpression is frequently detected in tumour-free tonsil tissue without association with HPV.

AIMS: Oncogenic human papillomavirus (HPV) type 16 has been strongly associated with tonsillar squamous cell carcinoma (TSCC) and appears to be of prognostic significance. Because HPV+ TSCC also accumulates p16(INK4A), this cyclin-dependent kinase inhibitor has been proposed as a potential biomarker for HPV in clinical diagnosis. The aim of this study was to determine the prevalence of HPV in tumour-free tonsillar tissue and the value of p16(INK4A) overexpression in predicting its presence. METHODS AND RESULTS: p16(INK4A) overexpression was detected by immunohistochemistry in tissue sections of tumour-free tonsils of 262 patients. They were treated for non-oncological reasons (snoring or chronic/recurrent tonsillitis) consisting of tonsillectomy. Genomic DNA isolated from these tissues was subjected to HPV-specific polymerase chain reaction (PCR) analysis. p16(INK4A) immunoreactivity was detected in 28% of samples in both crypt epithelium (49/177) and lymphoid germinal centres (52/187), which correlated with each other (P < 0.0001). No reactivity was observed in superficial squamous cell epithelium. HPV16 and 18 were detected by PCR analysis in 2/195 cases (1%), which, however, were negative on fluorescence in situ hybridization analysis and discrepant on p16(INK4A) immunostaining. CONCLUSIONS: No proof was found for the presence of HPV in tumour-free tonsil tissue, despite increased p16(INK4A) expression in a quarter of tonsil cases. Other mechanisms than HPV infection are therefore implicated in p16(INK4A) up-regulation.

P21 Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis.

Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16(INK4A,) cyclin D1, pRb, p14(ARF), MDM2, p53, p21(Cip1/WAF1), and p27(KIP1). Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16(INK4A) overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14(ARF) (P<0.0001) and p21(Cip1/WAF1) (P=0.001), and downregulation of pRb (P<0.0001) and cyclin D1 (P=0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P=0.006), as well as for patients with T1-2 tumors (P<0.0001) or tumors showing low expression of cyclin D1 (P=0.028), presence of human papillomavirus and overexpression of p16(INK4A) (P=0.01), p14(ARF) (P=0.02) or p21(Cip1/WAF1) (P=0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21(Cip1/WAF1), were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21(Cip1/WAF1) and p14(ARF) overexpression and downregulation of pRb and cyclin D1. In particular p21(Cip1/WAF1) overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas.