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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.

Patients undergoing major surgery experience postoperative inflammation, which may contribute to postoperative morbidity. Endogenous glucocorticoids (GCs) are an essential part of the stress response, but this response varies between individuals, which may in turn affect clinical outcome and specifically postoperative inflammation. Exon 1 of the NR3C1 gene, encoding the GC receptor (GR), contains an established region of differential regulation. DNA methylation patterns in this region have been found to differ between individuals. The present study investigated the methylation status and genotype in the cytosine-phosphate-guanine (CpG) island in exon 1 of NR3C1 in 24 patients [Median age 65.5 (range 42–81) years, 11 male, 13 female] who underwent major abdominal (12 pancreatic, 12 hepatic) surgery and explored its association with postoperative complications. DNA was extracted from peripheral blood leukocytes and underwent targeted bisulfite sequencing of the CpG island. Complications were graded according to the Clavien-Dindo classification and 14 out of 24 patients had postoperative complications. Multifactorial and partial least square analyses were used to analyse the data. A homogenous demethylated pattern was observed in all patients and no single CpG methylation was associated with postoperative complications. Four SNPs were significantly associated with higher Clavien-Dindo scores. Genetic variability in the chromosome 5:143,402,505–143,405,805 region of exon 1 of the GR gene NR3C1, but not DNA methylation, was associated with more severe postoperative complications in patients having major abdominal surgery. These results indicated that the patients' response to GCs may be of clinical importance for inflammatory conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Environmental risk factors together with genetic vulnerability create a complex background to develop depression. Methods: We investigated the associations between COMT Val158Met and depression in a Swedish population-based sample of 405 depressed individuals (major depression diagnosis, dysthymia or mixed anxiety depression defined according to DSM-IV) and 2,151 healthy controls. We also analyzed interaction between this genetic variation and some environmental risk factors for depression and the link between this polymorphism and the low motivational level and negative mood state found in depressed individuals. Results: Depressed individuals displayed a higher frequency of the Met/Met and Met/Val genotypes compared to controls (OR=1.49, CI95% =1.11–2.00, P=0.009). The association was found among men only (OR=2.26, CI95% =1.26–4.05, p=0.008). Regression analysis including some potential risk factors for depression, did further indicate that Met/Met and Met/Val were associated with depression in men (P=0.005). There was also an interaction between genotype and family childhood problems (RERI=0.876, CI95% =0.090–1.662 and AP=0.426, CI95% =0.030–0.821). Further, depressed men homozygous for the Val-allele, had a higher motivational level than depressed men with a Met-variant (P=0.02). Limitations: The sample size of depressed individuals per group when stratifying cases according to gender and genotypes is considered a limitation. Conclusions: The Met-variants of COMT Val158Met are risk variants for depression and low motivational level in depressed Swedish men, but not women. Individuals with this risk variant in combination with a problematic childhood, have an even higher risk to develop depression. [Copyright &y& Elsevier]

Alcohol misuse is a major public health problem originating from genetic and environmental risk factors. Alterations in the brain epigenome may orchestrate changes in gene expression that lead to alcohol misuse and dependence. Through epigenome-wide association analysis of DNA methylation from human brain tissues, we identified a differentially methylated region, DMR-DLGAP2, associated with alcohol dependence. Methylation within DMR-DLGAP2 was found to be genotype-dependent, allele-specific and associated with reward processing in brain. Methylation at the DMR-DLGAP2 regulated expression of DLGAP2 in vitro, and Dlgap2-deficient mice showed reduced alcohol consumption compared with wild-type controls. These results suggest that DLGAP2 may be an interface for genetic and epigenetic factors controlling alcohol use and dependence., (© 2019. The Author(s), under exclusive licence to Springer Nature Limited.)

The study of epigenetic alterations of the genome is becoming increasingly important in order to understand how environment and genetic background interact to build and regulate the functional genome. There are several types of epigenetic modifications to both DNA and histone proteins in eukaryotic cells; chiefly studied among these are changes to cytosine, where methylation of the 5-carbon position is the most prominent. Although this has many consequences for gene regulation and cell differentiation, other modifications have recently emerged as biologically relevant. Since global DNA methylation states may be used as a general measure of the methylome, cost-effective, rapid, and specific analytical tools are wanted.This protocol described here focuses on the Luminometric Methylation Assay (LUMA), a method which analyzes global DNA 5-methylcytosine (5mC) through the use of restriction enzymes and detection with Pyrosequencing(®). Up to 96 samples can be simultaneously analyzed. In contrast to the majority of other methods focused on 5mC analysis, with appropriate enzymes, LUMA does not appear to detect 5-hydroxymethylcytosine (5hmC) and is therefore more specific than most 5mC techniques.

The circadian clock is driven by transcription-translation feedback loops and regulates rhythms that approximate the 24-hr day-night cycle or light-dark transitions. Disruptions of the circadian rhythms are common in depressed patients, expressed for example as sleep disturbances. Genetic variations in core circadian genes may in part explain these abnormalities. To investigate whether genetic variation in core circadian genes associates with vulnerability to depression, we genotyped 18 genes in a Swedish population based sample. Genetic variations indicative of association with depression, or with winter depression in our previous study, were tested for association to depression in a second Swedish depression-control sample set. PER2 genetic variation was associated with depression vulnerability, and this genetic risk did not seem to require exposure to potential sleep disturbance factors such as negative life event or financial strain that are known to increase the risk for depression. Polymorphisms in the circadian genes NPAS2, ARNTL, and RORA were also suggested to contribute to depression vulnerability. The findings we report for PER2, ARNTL, and RORA are supported by at least two of the three sample sets. In conclusion, genetic variation in PER2 is associated with depression vulnerability a Swedish population-based sample. More studies are needed to determine if this is the case also for NPAS2, ARNTL, and RORA., ((c) 2009 Wiley-Liss, Inc.)