Even though schizophrenia has a strong hereditary component, departures from simple genetic transmission are prominent. DNA methylation has emerged as an epigenetic explanatory candidate of schizophrenia's nonmendelian characteristics. To investigate this assumption, we examined genome-wide (global) and gene-specific DNA methylation levels, which are associated with genomic stability and gene expression activity, respectively. Analyses were conducted using DNA from leukocytes of patients with schizophrenia and controls. Global methylation results revealed a highly significant hypomethylation in patients with schizophrenia (P<2.0×10(-6)) and linear regression among patients generated a model in which antipsychotic treatment and disease onset explained 11% of the global methylation variance (adjusted R(2)=0.11, ANOVA P<0.001). Specifically, haloperidol was associated with higher ("control-like") methylation (P=0.001), and early onset (a putative marker of schizophrenia severity) was associated with lower methylation (P=0.002). With regard to the gene-specific methylation analyses, and in accordance with the dopamine hypothesis of psychosis, we found that the analyzed region of S-COMT was hypermethylated in patients with schizophrenia (P=0.004). In summary, these data support the notion of a dysregulated epigenome in schizophrenia, which, at least globally, is more pronounced in early-onset patients and can be partly rescued by antipsychotic medication. In addition, blood DNA-methylation signatures show promise of serving as a schizophrenia biomarker in the future.-Melas, P. A., Rogdaki, M., Ösby, U., Schalling, M., Lavebratt, C., Ekström, T. J. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset.

Neuropeptide Y (NPY) is known to influence emotional processing and decreased NPY levels have been associated with mood and anxiety disorders. Alternative splicing of pre-messenger RNA is a cellular mechanism that allows for transcriptome diversity, yet there is limited knowledge in this respect with regard to Npy. Since the hippocampus and the prefrontal cortex play an important role in affective disorders, we investigated alternative splicing of Npy in these regions of a rat model of depression (Flinders Sensitive Line, FSL) and its controls (Flinders Resistant Line, FRL). The existence of different Npy messenger RNA (mRNA) variants was examined using 5' and 3' RACE. In addition to the Npy mRNA species annotated in GenBank and Ensembl, we identified a novel "short" mRNA splice variant. Immunoblotting results argued against a putative translation of this "short" mRNA into protein in brain tissue. Compared to the FRL, the FSL had reduced "short"Npy mRNA levels in the HIP (P=0.00014) and the PFC (P=0.016). Gene expression analyses in five brain regions of an outbred rat strain supported the presence of the "short"Npy transcript in all examined regions and showed that it is expressed in ∼2.4-fold lower levels than the "long"Npy mRNA. Finally, sequencing of the 5' RACE products revealed a transcription start site of Npy that is different from the currently annotated position. These data add to the characterization of the rat Npy mRNA and demonstrate the presence of a novel transcript with a so far unknown function.

Current therapies and research for epilepsy concentrate mainly on controlling the disease, but not on prevention of its development and progression. This is partly due to the under-appreciated heterogeneity of the different epileptic syndromes, and a lack of knowledge about the underlying mechanisms of hypersensitivity and hypersynchrony in epilepsy development and spread. In this study we investigate mechanisms underlying the increased susceptibility to acoustic startle in a mouse model homozygous for the spontaneous megencephaly (mceph) mutation, which results in a lack of the functional potassium channel Kv1.1. Mceph mice are hypersensitive to acoustic startle, a response that is not seen in the wild-type (WT) littermates. After acoustic startle, a strong activation of astrocytes, as indicated by glial fibrillary acidic protein, occurred in the inferior colliculus and hippocampus. Both the hypersensitivity of acoustic startle as well as activation of astrocytes could be maintained at WT levels by pre-treating the Mceph mice with the anti-epileptic drug valproate. Furthermore, we utilized the Mceph mouse model to investigate whether acoustic startle-induced hypersensitivity has negative consequences for synchronous neuronal activity in other, non-auditory, systems and networks in the brain, such as the hippocampus. Our findings show that acoustic startle-induced hypersensitivity primes hippocampal networks by increasing their excitability, which results in increased strength of rhythmic network activity. Our results provide novel insights into the mechanisms that underlie the spread of hypersensitivity and hypersynchrony across functionally different parts of the brain.

The availability to the DNA strand and the activity of the transcription machinery is crucial for the cell to use the information in the DNA. The epigenetic mechanisms DNA methylation, modification of histone tails, other chromatin-modifying processes and interference by small RNAs regulate the cell-type-specific DNA expression. Epigenetic marks can be more or less plastic perpetuating responses to various molecular signals and environmental stimuli, but in addition apparently stochastic epigenetic marks have been found. There is substantial evidence from animal and man demonstrating that both transient and more long-term epigenetic mechanisms have a role in the regulation of the molecular events governing adipogenesis and glucose homeostasis. Intrauterine exposure such as poor maternal nutrition has consistently been demonstrated to contribute to a particular epigenotype and thereby developmental metabolic priming of the exposed offspring in animal and man. Epigenetic modifications can be passed not only from one cell generation to the next, but metabolic disease-related epigenotypes have been proposed to also be transmitted germ-line. Future more comprehensive knowledge on epigenetic regulation will complement genome sequence data for the understanding of the complex etiology of obesity and related disorder.International Journal of Obesity advance online publication, 13 September 2011; doi:10.1038/ijo.2011.178.

P11 (S100A10) has been associated with the pathophysiology of depression both in human and rodent models. Different types of antidepressants have been shown to increase P11 levels in distinct brain regions and P11 gene therapy was recently proven effective in reversing depressive-like behaviours in mice. However, the molecular mechanisms that govern P11 gene expression in response to antidepressants still remain elusive. In this study we report decreased levels of P11, associated with higher DNA methylation in the promoter region, in the prefrontal cortex of the Flinders Sensitive Line (FSL) genetic rodent model of depression. This hypermethylated pattern was reversed to normal, as indicated by the control line, after chronic administration of escitalopram (a selective serotonin reuptake inhibitor; SSRI). The escitalopram-induced hypomethylation was associated with both an increase in P11 gene expression and a reduction in mRNA levels of two DNA methyltransferases that have been shown to maintain DNA methylation in adult forebrain neurons (Dnmt1 and Dnmt3a). In conclusion, our data further support a role for P11 in depression-like states and suggest that this gene is controlled by epigenetic mechanisms that can be affected by antidepressant treatment.

Voltage-dependent K(+) channels (Kv) mediate repolarisation of β-cell action potentials, and thereby abrogate insulin secretion. The role of the Kv1.1 K(+) channel in this process is however unclear. We tested for presence of Kv1.1 in different species and tested for a functional role of Kv1.1 by assessing pancreatic islet function in BALB/cByJ (wild-type) and megencephaly (mceph/mceph) mice, the latter having a deletion in the Kv1.1 gene. Kv1.1 expression was detected in islets from wild-type mice, SD rats and humans, and expression of truncated Kv1.1 was detected in mceph/mceph islets. Full-length Kv1.1 protein was present in islets from wild-type mice, but, as expected, not in those from mceph/mceph mice. Kv1.1 expression was localized to the β-cell population and also to α- and δ-cells, with evidence of over-expression of truncated Kv1.1 in mceph/mceph islets. Blood glucose, insulin content, and islet morphology were normal in mceph/mceph mice, but glucose-induced insulin release from batch-incubated islets was (moderately) higher than that from wild-type islets. Reciprocal blocking of Kv1.1 by dendrotoxin-K increased insulin secretion from wild-type but not mceph/mceph islets. Glucose-induced action potential duration, as well as firing frequency, was increased in mceph/mceph mouse β-cells. This duration effect on action potential in β-cells from mceph/mceph mice was mimicked by dendrotoxin-K in β-cells from wild-type mice. Observations concerning the effects of both the mceph mutation, and of dendrotoxin-K, on glucose-induced insulin release were confirmed in pancreatic islets from Kv1.1 null mice. Kv1.1 channels are expressed in the β-cells of several species, and these channels can influence glucose-stimulated insulin release.

BACKGROUND: Genetic variations in FKBP5, BDNF, P2RX7 and CACNA1 are current candidates for involvement in depression. METHODS: The single nucleotide polymorphisms FKBP5:rs1360780, BDNF:rs6265 (Val66Met), P2RX7:2230912 (Gln460Arg) and CACNA1C:rs1006737 were genotyped in DNA from 457 depression cases (major depression, dysthymia, and mixed anxiety depression) and 2286 healthy controls with no symptom of psychopathology. Cases and controls were derived from a large well-characterized longitudinal population-based sample of adult Swedes with data on life situation and life history. Association to depression was analyzed with and without consideration to problems during childhood and negative life events last year. RESULTS: FKBP5:rs1360780 allele T and genotype TT were overrepresented in depression for men. Childhood problems and negative life events (two or more) conferred a risk for depression (OR=2.8, 95% CI: 2.2-3.5 and OR=2.9, 95% CI: 2.4-3.7, respectively). The BDNF:rs6265 Met-allele was overrepresented in depression for women with problems during their childhood. No indication for association to depression was found for P2RX7:2230912 and CACNA1C:rs1006737 without or with consideration of childhood problems or negative life events. LIMITATIONS: The sample size did not allow exclusion of true association to depression at low odds ratios. There was possibly some recall bias of childhood problems. CONCLUSIONS: These data support previous reports on FKBP5:rs1360780 and show a gender difference. Likewise, they support previous reports on BDNF:rs6265 and show involvement of environmental stress. P2RX7:2230912 and CACNA1C:rs1006737 did not have a large or moderate-size effect on depression risk. Further studies are required to estimate the significance of these findings.

BACKGROUND: Abnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated. PRINCIPAL FINDINGS: We observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively). CONCLUSIONS: We propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression.

ABSTRACT: BACKGROUND: Depression and alcohol abuse or dependence (AUD) co-occur in the general population more frequently than expected by chance. Alcohol use influences the circadian rhythms generated by the central pacemaker in the suprachiasmatic nucleus, and circadian rhythm alterations in turn are common in depressive disorders as well as among persons addicted to alcohol. METHODS: 32 SNPs in 19 circadian clockwork related genes were analyzed using DNA from 76 individuals with comorbid depression and AUD, 446 individuals with AUD and 517 healthy controls with no psychiatric diagnosis. The individuals participated in a nationwide health examination study, representative of the general population aged 30 and over in Finland. RESULTS: The CLOCK haplotype TTGC formed by SNPs rs3805151, rs2412648, rs11240 and rs2412646, was associated with increased risk for comorbidity (OR=1.65, 95% CI=1.14-2.28, P=0.0077). The SNPs of importance for this suggestive association were rs2412646 and rs11240 indicating location of the functional variation in the block downstream rs2412648. There was no indication for association between CLOCK and AUD. CONCLUSION: Our findings suggest an association between the CLOCK gene and the comorbid condition of alcohol use and depressive disorders. Together with previous reports it indicates that the CLOCK variations we found here may be a vulnerability factor to depression given the exposure to alcohol in individuals having AUD.

Objectives To investigate empirically the motivations for not consenting to DNA biobanking in a Swedish population-based study and to discuss the implications. Design Structured questionnaires and semistructured interviews. Setting A longitudinal epidemiological project (PART) ongoing since 1998 in Stockholm, Sweden. The DNA-collection wave took place during 2006-7. Participants 903 individuals completed the questionnaire (participation rate 36%) and 23 were interviewed. All individuals had participated in both non-genetic waves of the project, but refused to contribute saliva samples during the DNA-collection wave. Main outcome measures Motivations behind refusing to consent to DNA biobanking, with subsequent focus on participants' explanations regarding this unwillingness. Results Public refusal to consent to DNA biobanking, as revealed by the questionnaire, was mainly explained by a lack of personal relevance of DNA contribution and feelings of discomfort related to the DNA being used for purposes other than the respective study. Interviews of individuals representing the second motivation, revealed a significant mistrust of DNA biobank studies. The underlying beliefs and attitudes were associated with concerns about integrity, privacy, suspiciousness and insecurity. However, most interviewees were supportive of genetic research per se and interpreted their mistrust in the light of distressing environmental influences. Conclusion The results suggest a need for guidelines on benefit sharing, as well as trustworthy and stable measures to maintain privacy, as a means for increasing personal relevance and trust among potential participants in genetic research. Measures taken from biobanks seem insufficient in maintaining and increasing trust, suggesting that broader societal measures should be taken.