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 variable distribution 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: 291 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 modelled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were modelled 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).Conclusions: Our results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on the other etiological factors involved. This finding requires further validation in other large independent cohorts. Potentially this work could have translational implications, as the ability to discriminate between genetic etiologies, based on a case-by-case understanding of exposure history would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategie

Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic:Mechanisms of Psychosis Risk

Associations between influenza infection and psychosis have been reported since the eighteenth century, with acute “psychoses of influenza” documented during multiple pandemics. In the late 20th century, reports of a season-of-birth effect in schizophrenia were supported by large-scale ecological and sero-epidemiological studies suggesting that maternal influenza infection increases the risk of psychosis in offspring. We examine the evidence for the association between influenza infection and schizophrenia risk, before reviewing possible mechanisms via which this risk may be conferred. Maternal immune activation models implicate placental dysfunction, disruption of cytokine networks, and subsequent microglial activation as potentially important pathogenic processes. More recent neuroimmunological advances focusing on neuronal autoimmunity following infection provide the basis for a model of infection-induced psychosis, potentially implicating autoimmunity to schizophrenia-relevant protein targets including the N-methyl-D-aspartate receptor. Finally, we outline areas for future research and relevant experimental approaches and consider whether the current evidence provides a basis for the rational development of strategies to prevent schizophrenia.</p

Associations between the schizophrenia susceptibility gene ZNF804A and clinical outcomes in psychosis

We sought to test the hypothesis that the rs1344706 A allele will be associated with worse clinical outcome in first-episodepsychosis. A data linkage was set up between a large systematic study of first-episode psychosis and an electronic health-recordcase register at the South London and Maudsley NHS Foundation Trust—a large provider of secondary mental-health care. Asample of 291 patients, who presented with a first psychotic episode (ICD10 diagnoses F20–29 or F30–33) and in whom thers1344706 genotype had been assayed, were followed to examine the duration of mental-health in-patient care during the 2 yearsfollowing first service contact, as a primary outcome. Secondary outcome measures were whether or not an in-patient episodeoccurred and the number of in-patient episodes during this period. A strong association was found between the number ofrs1344706 A alleles and the cumulative duration of mental-health in-patient stay over the 2 years since initial presentation. In the84.2% who experienced an in-patient episode during this period, the mean duration of admission was an additional 38 days foreach A allele increment. Therefore, in addition to its potential role as a risk factor for psychosis, the ZNF804A rs1344706 A allele isassociated with worse clinical outcome

Cell- and single molecule-based methods to detect Anti-N-Methyl-D-Aspartate receptor autoantibodies in first episode psychosis patients from the OPTiMiSE project

Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR-Ab) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating NMDAR-Ab in psychotic disorders remains controversial with detection prevalence rates, and immunoglobulin (Ig) classes, varying considerably between studies, perhaps because of different detection methods. Here, we compared the results of serum assays for a large cohort of first episode psychosis patients (FEP) using classical cell-based assays in three labs and a single molecule-based imaging method. Most assays and single molecule imaging in live hippocampal neurons revealed the presence of circulating NMDAR-Ab in approximately 5% of FEP patients. However, some heterogeneity between cell-based assays was clearly observed, highlighting the urgent need of new sensitive methods to detect the presence of low-titer NMDAR-Ab in seropositive patients that cannot be clinically identified from seronegative ones

Interaction between childhood adversity and functional polymorphisms in the dopamine pathway on first-episode psychosis

Background: There is consistent evidence of a cumulative relationship between childhood adversity and psychosis, with number of adversities experienced increasing the probability of psychosis onset. It is possible that genetic factors moderate the association between childhood adversity and psychosis, potentially by influencing how an individual reacts biologically and/or psychologically following exposure to adversity, in such a way as to set them off on the path to psychosis. However, identifying the specific genetic variants involved and how they interact with childhood adversity remains challenging. We examined whether the association between cumulative exposure to childhood adversity and development of psychotic disorder was moderated by the COMT Val158Met, AKT1 rs2494732 or DRD2 rs1076560 polymorphisms, known to affect dopamine levels. Methods: Participants were 285 first-presentation psychosis cases and 256 geographically-matched controls drawn from the Genetics and Psychosis (GAP) study. Childhood adversity was assessed using the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and blood- and cheek-derived genotype data were collected.Results: Our findings revealed no main effect of COMT Val158Met, AKT1 rs2494732 and DRD2 rs1076560 polymorphisms on psychosis case status or reports of childhood adversity. Individuals reporting a history of multiple adversities were more likely to be psychosis patients than controls, regardless of their genetic risk. There was no evidence of candidate genotype by childhood adversity interactions in relation to psychosis onset. Conclusion: These findings did not provide evidence of a possible role of COMT Val158Met, AKT1 rs2494732 or DRD2 rs1076560 genotypes in modifying the association between childhood adversity and onset of psychosis

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis us

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use.</p

Differential gene expression analysis in blood of first episode psychosis patients

Background: Psychosis is a condition influenced by an interaction of environmental and genetic factors. Gene expression studies can capture these interactions; however, studies are usually performed in patients who are in remission. This study uses blood of first episode psychosis patients, in order to characterise deregulated pathways associated with psychosis symptom dimensions. Methods: Peripheral blood from 149 healthy controls and 131 first episode psychosis patients was profiled using Illumina HT-12 microarrays. A case/control differential expression analysis was performed, followed by correlation of gene expression with positive and negative syndrome scale (PANSS) scores. Enrichment analyses were performed on the associated gene lists. We test for pathway differences between first episode psychosis patients who qualify for a Schizophrenia diagnosis against those who do not. Results: A total of 978 genes were differentially expressed and enriched for pathways associated to immune function and the mitochondria. Using PANSS scores we found that positive symptom severity was correlated with immune function, while negative symptoms correlated with mitochondrial pathways. Conclusions: Our results identified gene expression changes correlated with symptom severity and showed that key pathways are modulated by positive and negative symptom dimensions.</p