No Association between Genetic or Epigenetic Variation in Insulin Growth Factors and Antipsychotic-Induced Metabolic Disturbances in a Cross-Sectional Sample

Moons, Tim; Hert, Marc De; Kenis, G.; Viechtbauer, Wolfgang; Os, Jim van; Gohlke, Henning; Claes, Stephan; Winkel, Ruud van

doi:10.2217/pgs.14.46

Cited by 7 publications

(7 citation statements)

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“…Further work is needed in this area to begin to truly analyze pharmacoepigenetic-directed DNA methylation changes in bipolar disorder. Within schizophrenia, the main utilizers of SGAs, candidate epigene analyses have yielded mixed results when correlating methylation differences to metabolic outcomes [19,38–40] . We previously identified global hypomethylation in female schizophrenia subjects using the linear interspersed nuclear elements 1 (LINE1) assay [39] .…”

Section: Discussionmentioning

confidence: 99%

“…In the only other study to investigating gene-specific methylation in SGA-induced metabolic side effects in severe mental illness [40] , Moons and colleagues, found no associations between DNA methylation of IGF genes 1 or 2 and metabolic side effects. However, they did identify associations between variants within the IGF genes and IGF methylation which may suggest a link between DNA variation and DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Aims This study aimed to assess the effect of second-generation antipsychotic (SGA) use and insulin resistance on a global measure of DNA methylation in patients diagnosed with bipolar disorder. Materials & Methods Subjects stable on medication (either mood stabilizer monotherapy or adjuvant SGAs) were assessed for insulin resistance. Global methylation levels were assessed in leukocyte DNA from whole blood using the Luminometric Methylation Assay. Multivariable linear regression was used to investigate the effect of insulin resistance and SGA use on DNA methylation. Results A total of 115 bipolar I subjects were included in this study. The average age was 43.1 ±12.2 years and 73% were on SGAs. Average% global methylation was 77.0 ± 3.26 and was significantly influenced by insulin resistance, SGA use and smoking. Conclusion This is the first study to show a relationship between SGA use, insulin resistance and global DNA methylation. Further work will be needed to identify tissue- and gene-specific methylation changes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…This hypothesis was supported by identified associations between a global measure of DNA methylation and AAP‐induced insulin resistance within bipolar disorder . In the only candidate gene study to date, Moons and colleagues found no associations between AAP‐induced metabolic side effects and genetic or epigenetic variability in the insulin‐like growth factor 2 ( IGF2 ) gene …”

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confidence: 98%

Gene‐specific DNA methylation may mediate atypical antipsychotic‐induced insulin resistance

et al. 2016

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Objectives Atypical Antipsychotics (AAPs) carry a significant risk of cardiometabolic side effects including insulin resistance. It is thought that the insulin resistance resulting from the use of AAP may be associated with changes in DNA methylation. We aimed to identify and validate a candidate gene associated with AAP-induced insulin resistance by using a multi-step approach that included an epigenome-wide association study (EWAS) and validation with site-specific methylation and metabolomics data. Methods Bipolar subjects treated with AAPs or lithium monotherapy were recruited for a cross-sectional visit to analyze peripheral blood DNA methylation and insulin resistance. Epigenome-wide DNA methylation was analyzed in a discovery sample (n=48) using the Illumina 450K BeadChip. Validation analyses of the epigenome-wide findings occurred in a separate sample (n=72) using site-specific methylation with pyrosequencing and untargeted metabolomics data. Regression analyses were conducted controlling for known confounders in all analyses and a mediation analysis was performed to investigate if AAP-induced insulin resistance occurs through changes in DNA methylation. Results A differentially methylated probe associated with insulin resistance was discovered and validated in the Fatty Acyl CoA Reductase 2 (FAR2) gene of Chromosome 12. Functional associations of this DNA methylation site on untargeted phospholipid-related metabolites were also detected. Our results identified a mediating effect of this FAR2 methylation site on AAP-induced insulin resistance. Conclusions Going forward, prospective, longitudinal studies assessing comprehensive changes in FAR2 DNA methylation, expression, and lipid metabolism before and after AAP treatment are required to assess its potential role in the development of insulin resistance.

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“…Our systematic review yielded 29 studies (Table 1). Eighteen studies analyzed methylation in patients with schizophrenia, four studies in patients with bipolar disorder, and seven studies in a combined sample of patients with schizophrenia and bipolar disorder. The majority (n=22) of studies included observational sampling, such as cross‐sectional or case‐control studies, and the remaining analyzed changes in a prospective manner.…”

Section: Resultsmentioning

confidence: 99%

“…The most commonly employed measurement utilized restriction enzymes (five studies) followed by transposable elements (two studies) and ELISA (one study). 26 Obs 133 SCZ AAP and TAP Blood Global Cheng et al 27 Obs and prosp 30 Obs 172 BD olanzapine and quetiapine Blood d EWAS and genespecific Kinoshita et al 31 Prosp 21 SCZ olanzapine Blood EWAS Li et al 32 Obs 92 SCZ; 99 BD; 92 HC AAP and TAP Blood global Lott et al 33 Obs 85 SCZ NR blood gene-specific Melas et al 34 Obs 177 SCZ; 171 HC AAP and TAP Blood Global and genespecific Mill et al 35 Obs 35 SZ; 35 BD; 35 HC NR Brain EWAS Miura et al 36 Prosp 34 SCZ risperidone Blood Gene-specific Moons et al 37 Obs 438 SCZ AAP and TAP Blood Gene-specific Nour El Huda et al 38 Obs 138 SCZ; 132 HC AAP and TAP Blood Gene-specific Rukova et al 39 Prosp 20 SCZ; 220 HC NR Blood EWAS Shi et al 40 Prosp 288 SCZ risperidone Blood Gene-specific Swathy et al 41 Obs 184 SCZ; 330 HC NR Blood Global Tang et al 42 Prosp 82 SCZ AAP and TAP Blood Gene-specific Venugopal et al 43 Prosp 47 SCZ; 47 HC AAP Blood Gene-specific Zong et al 44 Obs 279 SCZ; 265 HC AAP and TAP Blood Gene-specific Details of 29 studies included in the systematic review including study design, type of antipsychotic within study, sample type for DNA methylation analysis, and overall DNA methylation strategy. AAP = atypical antipsychotic; BD = bipolar disorder; HC = healthy control; MDD = major depressive disorder; NR = not reported; obs = observational; PR = primary relative; pros = prospective; scz = schizophrenia; TAP = typical antipsychotic; UPR = unaffected primary relative.…”

Section: Global Methylation Studiesmentioning

confidence: 99%

Antipsychotic Medications and DNA Methylation in Schizophrenia and Bipolar Disorder: A Systematic Review

et al. 2020

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The pharmacoepigenetics of antipsychotic treatment in severe mental illness is a growing area of research that aims to understand the interface between antipsychotic treatment and genetic regulation. Pharmacoepigenetics may some day assist in identifying treatment response mechanisms or become one of the components in the implementation of precision medicine. To understand the current evidence regarding the effects of antipsychotics on DNA methylation a systematic review with qualitative synthesis was performed through Pubmed, Embase and Psychinfo from earliest data to June 2019. Studies were included if they analyzed DNA methylation in an antipsychotic‐treated population of patients with schizophrenia or bipolar disorder. Data extraction occurred via a standardized format and study quality was assessed. Twenty‐nine studies were identified for inclusion. Study design, antipsychotic type, sample source, and methods of DNA methylation measurement varied across all studies. Eighteen studies analyzed methylation in patients with schizophrenia, four studies in patients with bipolar disorder, and seven studies in a combined sample of schizophrenia and bipolar disorder. Twenty‐two studies used observational samples whereas the remainder used prospectively treated samples. Six studies assessed global methylation, five assessed epigenome‐wide, and 15 performed a candidate epigenetic study. Two studies analyzed both global and gene‐specific methylation, whereas one study performed a simultaneous epigenome‐wide and gene‐specific study. Only three genes were analyzed in more than one gene‐specific study and the findings were discordant. The state of the pharmacoepigenetic literature on antipsychotic use is still in its early stages and uniform reporting of methylation site information is needed. Future work should concentrate on using prospective sampling with appropriate control groups and begin to replicate many of the novel associations that have been reported.

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No Association between Genetic or Epigenetic Variation in Insulin Growth Factors and Antipsychotic-Induced Metabolic Disturbances in a Cross-Sectional Sample

Abstract: There was a significant association between IGF2 methylation and genotype, but no significant association between genetic or epigenetic variability and metabolic parameters in the present study.

Cited by 7 publications

References 88 publications

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

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

Gene‐specific DNA methylation may mediate atypical antipsychotic‐induced insulin resistance

Antipsychotic Medications and DNA Methylation in Schizophrenia and Bipolar Disorder: A Systematic Review

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