Role of Environmental Confounding in the Association between FKBP5 and First-Episode Psychosis.

BACKGROUND: Failure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level. METHODS: Two hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis. RESULTS: Association at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23-6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95). CONCLUSION: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.

Life events and psychosis: a review and meta-analysis.

INTRODUCTION: Recent models of psychosis implicate stressful events in its etiology. However, while evidence has accumulated for childhood trauma, the role of adult life events has received less attention. Therefore, a review of the existing literature on the relationship between life events and onset of psychotic disorder/experiences is timely. METHODS: A search was conducted using PsychInfo, Medline, Embase, and Web of Science to identify studies of life events and the onset of psychosis or psychotic experiences within the general population. Given previous methodological concerns, this review included a novel quality assessment tool and focused on findings from the most robust studies. A meta-analysis was performed on a subgroup of 13 studies. RESULTS: Sixteen studies published between 1968 and 2012 were included. Of these, 14 reported positive associations between exposure to adult life events and subsequent onset of psychotic disorder/experiences. The meta-analysis yielded an overall weighted OR of 3.19 (95% CI 2.15-4.75). However, many studies were limited by small sample sizes and the use of checklist measures of life events, with no consideration of contextual influences on the meaning and interpretation of events. CONCLUSIONS: Few studies have assessed the role of adult life events in the onset of psychosis. There was some evidence that reported exposure to adult life events was associated with increased risk of psychotic disorder and subclinical psychotic experiences. However, the methodological quality of the majority of studies was low, which urges caution in interpreting the results and points toward a need for more methodologically robust studies.

A systematic review of the activity of the hypothalamic-pituitary-adrenal axis in first episode psychosis.

Up to now studies on hypothalamic-pituitary-adrenal (HPA) axis activity in psychosis have shown inconsistent findings. These inconsistencies have been often ascribed to confounding effects of long duration of illness and chronic treatment with psychotropic medications of the subjects studied (chronic psychosis). In the last years, several studies have focused on the study of subjects at their first episode of psychosis to overcome these possible confounders. The aim of this paper was to review the literature investigating HPA axis activity in first episode psychosis. Findings from these studies support the presence of HPA axis hyperactivity and a blunted HPA axis response to stress at the onset of psychosis. Possible biological pathways linking these HPA axis abnormalities to the development of psychosis are discussed.

Kinetic properties of p53 phosphorylation by the human vaccinia-related kinase 1.

The vaccinia-related kinase 1 (VRK1) protein is a nuclear Ser-Thr kinase that phosphorylates p53 in Thr18. We have determined the enzyme properties regarding its different substrates. VRK1 has a high affinity for ATP (K(m) 50 microM) and is thus saturated by the intracellular concentration of ATP in vivo. VRK1 uses preferentially magnesium, but is also functional with manganese and zinc. The VRK1 protein is autophosphorylated in multiple residues without effect on its activity. One autophosphorylated residue, T355, is within the VRK1 regulatory carboxy terminus. The kinase phosphorylates p53 with a K(m) of 1 microM and is well suited to respond to the variations of intracellular p53 concentration, which fluctuates as a response to different types of cellular stress.