Effects of common GRM5 genetic variants on cognition, hippocampal volume and mGluR5 protein levels in schizophrenia.

GRM5 (coding for metabotropic glutamate receptor 5, mGluR5) is a promising target for the treatment of cognitive deficits in schizophrenia, but there has been little investigation of its association with cognitive and brain phenotypes within this disorder. We examined the effects of common genetic variation in GRM5 with cognitive function, hippocampal volume, and hippocampal mGluR5 protein levels in schizophrenia patients relative to healthy controls. Two independent GRM5 variants rs60954128 [C>T] and rs3824927 [G>T] were genotyped in a schizophrenia case/control cohort (n=249/261). High-resolution anatomical brain scans were available for a subset of the cohort (n=103 schizophrenia /78 control). All participants completed a standard set of neuropsychological tests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippocampal mGluR5 protein levels were examined among individuals of different GRM5 genotypes. Schizophrenia minor allele carriers of rs60954128 had reduced right hippocampal volume relative to healthy controls of the same genotype (-12.3%); this effect was exaggerated in males with schizophrenia (-15.6%). For rs3824927, compared to major allele homozygotes, minor allele carriers with schizophrenia had lower Intelligence Quotients (IQ). Examination in hippocampal postmortem tissue showed no difference in mGluR5 protein expression according to genotype for either rs60954128 or rs3824927. While these genetic variants in GRM5 were associated with cognitive impairments and right hippocampal volume reduction in schizophrenia, they did not affect protein expression. Further study of these mechanisms may help to delineate new targets for the treatment of cognitive deficits in schizophrenia, and may be relevant to other disorders.

Diurnal cortisol variation and cortisol response to an MRI stressor in schizophrenia and bipolar disorder.

Markers of HPA axis function, including diurnal cortisol rhythm and cortisol responses to stress or pharmacological manipulation, are increasingly reported as disrupted in schizophrenia (SZ) and bipolar disorder (BD). However, there has been no direct comparison of cortisol responses to stress in SZ and BD in the same study, and associations between cortisol dysfunction and illness characteristics remain unclear. In this study we used spline embedded linear mixed models to examine cortisol levels of SZ and BD participants at waking, during the first 45min after waking (representing the cortisol awakening response; CAR), during the period of rapid cortisol decline post the awakening response, and in reaction to a stressor (MRI scan), relative to healthy controls (HC). Contrary to expectations, neither SZ nor BD showed differences in waking cortisol levels, CAR, or immediate post-CAR decline compared to HC; however, waking cortisol levels were greater in BD relative to SZ. In response to the MRI stressor, the SZ group showed a significant absence of the expected increase in cortisol responsivity to stress, which was seen in both the BD and HC groups. Clinical factors affecting the CAR differed between SZ and BD. In SZ, higher antipsychotic medication dosage was associated with a steeper incline of the CAR, while greater positive symptom severity was associated with a more blunted CAR, and greater levels of anxiety were associated with the blunted cortisol response to stress. In BD, longer illness duration was associated with a steeper incline in CAR and lower levels of waking cortisol. These results suggest that cortisol responses may normalize with medication (in SZ) and longer illness duration (in BD), in line with findings of aberrant cortisol levels in the early stages of psychotic disorders.

DNA methylation in peripheral tissue of schizophrenia and bipolar disorder: a systematic review.

BACKGROUND: Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on findings in post-mortem brain tissue. A systematic review was conducted to synthesise and evaluate the quality of available evidence for epigenetic modifications (specifically DNA methylation) in peripheral blood and saliva samples of schizophrenia and bipolar disorder patients in comparison to healthy controls. METHODS: Original research articles using humans were identified using electronic databases. There were 33 included studies for which data were extracted and graded in duplicate on 22 items of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, to assess methodological precision and quality of reporting. RESULTS: There were 15 genome-wide and 18 exclusive candidate gene loci investigations for DNA methylation studies. A number of common genes were identified as differentially methylated in schizophrenia/bipolar disorder, which were related to reelin, brain-derived neurotrophic factor, dopamine (including the catechol-O-methyltransferase gene), serotonin and glutamate, despite inconsistent findings of hyper-, hypo-, or lack of methylation at these and other loci. The mean STROBE score of 59% suggested moderate quality of available evidence; however, wide methodological variability contributed to a lack of consistency in the way methylation levels were quantified, such that meta-analysis of the results was not possible. CONCLUSIONS: Moderate quality of available evidence shows some convergence of differential methylation at some common genetic loci in schizophrenia and bipolar disorder, despite wide variation in methodology and reporting across studies. Improvement in the clarity of reporting clinical and other potential confounds would be useful in future studies of epigenetic processes in the context of exposure to environmental and other risk factors.

Stress, schizophrenia and bipolar disorder.

The role of stress in precipitating psychotic episodes in schizophrenia and bipolar disorder has long been acknowledged. However, the neurobiological mechanism/s of this association have remained elusive. Current neurodevelopmental models of psychosis implicate early dysfunction in biological systems regulating hypothalamic-pituitary-adrenal axis and immune function, with long-term effects on the development of the brain networks responsible for higher order cognitive processes and stress reactivity in later life. There is also increasing evidence of childhood trauma in psychosis, and its impact on the development of brain systems regulating stress. These findings are emerging in the context of a new era of epigenetic methods facilitating the study of environmental effects on gene expression. The evidence is thus converging: exposure to stress at critical periods in life may be an important factor in the development of the brain dysfunction that represents psychosis vulnerability, rather than merely interacting with an independent 'biological vulnerability' to manifest in psychosis.