DNA methylation, insulin resistance and second-generation antipsychotics in bipolar disorder

Burghardt, Kyle J.; Goodrich, Jaclyn M.; Dolinoy, Dana C.; Ellingrod, Vicki L.

doi:10.2217/epi.15.5

Cited by 31 publications

(25 citation statements)

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“…None of these genes have been characterised in relation to insulin sensitivity. Neither PBMC, SAT nor VAT DNA methylation signatures could confirm the previously reported association of global leucocyte DNA methylation with IR [35]. Furthermore, a DMS in the ABCG1 gene in T cells that previously has been associated with HOMA-IR was not detected in the present study [13].…”

Section: Discussioncontrasting

confidence: 84%

The epigenetic signature of systemic insulin resistance in obese women

et al. 2016

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Aims/hypothesisInsulin resistance (IR) links obesity to type 2 diabetes. The aim of this study was to explore whether white adipose tissue (WAT) epigenetic dysregulation is associated with systemic IR by genome-wide CG dinucleotide (CpG) methylation and gene expression profiling in WAT from insulin-resistant and insulin-sensitive women. A secondary aim was to determine whether the DNA methylation signature in peripheral blood mononuclear cells (PBMCs) reflects WAT methylation and, if so, can be used as a marker for systemic IR.MethodsFrom 220 obese women, we selected a total of 80 individuals from either of the extreme ends of the distribution curve of HOMA-IR, an indirect measure of systemic insulin sensitivity. Genome-wide transcriptome and DNA CpG methylation profiling by array was performed on subcutaneous (SAT) and visceral (omental) adipose tissue (VAT). CpG methylation in PBMCs was assayed in the same cohort.ResultsThere were 647 differentially expressed genes (false discovery rate [FDR] 10%) in SAT, all of which displayed directionally consistent associations in VAT. This suggests that IR is associated with dysregulated expression of a common set of genes in SAT and VAT. The average degree of DNA methylation did not differ between the insulin-resistant and insulin-sensitive group in any of the analysed tissues/cells. There were 223 IR-associated genes in SAT containing a total of 336 nominally significant differentially methylated sites (DMS). The 223 IR-associated genes were over-represented in pathways related to integrin cell surface interactions and insulin signalling and included COL5A1, GAB1, IRS2, PFKFB3 and PTPRJ. In VAT there were a total of 51 differentially expressed genes (FDR 10%); 18 IR-associated genes contained a total of 29 DMS.Conclusions/interpretationIn individuals discordant for insulin sensitivity, the average DNA CpG methylation in SAT and VAT is similar, although specific genes, particularly in SAT, display significantly altered expression and DMS in IR, possibly indicating that epigenetic regulation of these genes influences metabolism.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4074-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussioncontrasting

confidence: 84%

The epigenetic signature of systemic insulin resistance in obese women

et al. 2016

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“…The effect of smoking on DNA methylation has been observed in several populations [65,66,67]. Additionally, cigarette smoking has been found to affect OXTR gene regulation and transcription in pregnant women [68].…”

Section: Discussionmentioning

confidence: 99%

Oxytocin Receptor <b><i>(OXTR)</i></b> Methylation and Cognition in Psychotic Disorders

et al. 2016

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Previous reports have identified an association between cognitive impairment and genetic variation in psychotic disorders. In particular, this association may be related to abnormal regulation of genes responsible for broad cognitive functions such as the oxytocin receptor (OXTR). Within psychotic disorders, it is unknown if OXTR methylation, which can have important implications for gene regulation, is related to cognitive function. The current study examined peripheral blood OXTR methylation and general cognition in people with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified (N = 101). Using hierarchical multiple regression analysis, methylation at the Chr3:8767638 site was significantly associated with composite cognitive performance independent of demographic and medication factors while controlling for multiple testing in this combined diagnostic sample (adjusted p = 0.023).

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“…Global methylation patterns have also been assessed in bipolar patients, and were shown to be significantly influenced by insulin resistance, second-generation antipsychotics use, and smoking (Burghardt et al, 2015). In an earlier study, no differences between bipolar patients and controls were found in leukocytes (Bromberg et al, 2009).…”

Section: Dna Methylation In Bdmentioning

confidence: 99%

“…However, a marked global hypermethylation has been reported in postmortem frontal cortex from affected individuals compared to controls (Rao et al, 2012a), while two other studies have reported a decrease in global methylation in transformed lymphoblasts (Huzayyin et al, 2014) and in whole blood from BD subjects (Soeiro-de-Souza et al, 2013). These discrepancies might be accounted for not only by the different populations studied, but also by the different methods used, which have been shown to vary significantly (Lisanti et al, 2013): three studies have assessed global methylation by ELISA (Huzayyin et al, 2014; Rao et al, 2012b; Soeiro-de-Souza et al, 2013), while others have used luminometric methylation assay (Burghardt et al, 2015) or cytokine-extension assay (Bromberg et al, 2009). Of note, the overall clinical relevance of alterations in global methylation still need to be determined.…”

Section: Dna Methylation In Bdmentioning

confidence: 99%

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

Fries

McAlpin

et al. 2016

Neuroscience & Biobehavioral Reviews

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Bipolar disorder (BD) is a multifactorial illness thought to result from an interaction between genetic susceptibility and environmental stimuli. Epigenetic mechanisms, including DNA methylation, can modulate gene expression in response to the environment, and therefore might account for part of the heritability reported for BD. This paper aims to review evidence of the potential role of DNA methylation in the pathophysiology and treatment of BD. In summary, several studies suggest that alterations in DNA methylation may play an important role in the dysregulation of gene expression in BD, and some actually suggest their potential use as biomarkers to improve diagnosis, prognosis, and assessment of response to treatment. This is also supported by reports of alterations in the levels of DNA methyltransferases in patients and in the mechanism of action of classical mood stabilizers. In this sense, targeting specific alterations in DNA methylation represents exciting new treatment possibilities for BD, and the ‘plastic’ characteristic of DNA methylation accounts for a promising possibility of restoring environment-induced modifications in patients.

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DNA methylation, insulin resistance and second-generation antipsychotics in bipolar disorder

Cited by 31 publications

References 50 publications

The epigenetic signature of systemic insulin resistance in obese women

The epigenetic signature of systemic insulin resistance in obese women

Oxytocin Receptor <b><i>(OXTR)</i></b> Methylation and Cognition in Psychotic Disorders

The role of DNA methylation in the pathophysiology and treatment of bipolar disorder

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