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

Abstract

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.

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

“…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.…”

“… a Burghardt et al studies assessed an independent bipolar population (Reference 22) and schizophrenia population (reference 23). …”

Dissecting the Epigenetic Changes Induced by Non-Antipsychotic Mood Stabilizers on Schizophrenia and Affective Disorders: A Systematic Review

“…Twenty-one described studies of rodent samples (Tremolizzo et al, 2002;Dong et al, 2005;Tremolizzo et al, 2005;Kim et al, 2008;Dong et al, 2010;Hobara et al, 2010;Perisic et al, 2010;Matrisciano et al, 2011;Wang et al, 2012;Zimmermann et al, 2012;Calabrese et al, 2013;Leng et al, 2013;Ookubo et al, 2013;Liu et al, 2014;Mackowiak et al, 2014;Balasubramanian et al, 2015;Bator et al, 2015;Dwivedi and Zhang, 2015;Lee et al, 2015;Leng et al, 2016;Bahna and Niles, 2017). Seven articles studied human cell lines (Asai et al, 2013;Kao et al, 2013;Dyrvig et al, 2017;Zong et al, 2017;Billingsley et al, 2018;Dyrvig et al, 2019;Manca et al, 2019) and eight focused on blood samples of subjects diagnosed with either of the selected psychiatric disorders (Gavin et al, 2009;D'Addario et al, 2012;Dell'Osso et al, 2014;Huzayyin et al, 2014;Burghardt et al, 2015;Burghardt et al, 2016;Houtepen et al, 2016;Bengesser et al, 2018). One article studied rodents and human cell lines and subjects (Kaminsky et al, 2015) and one focused on patients and human cell lines (Kakiuchi et al, 2003).…”

“…Association between specific drugs and loci methylation status did not provide any replication for the candidate genes after false discovery rate correction, most likely as a consequence of limited power. (Burghardt et al, 2016) Identify and validate a candidate gene associated with atypical antipsychoticsinduced insulin resistance through a cross sectional approach of subjects with BDI treated with Li monotherapy or atypical antipsychotics.…”

“…ARNTL, a core component of the circadian clock, is involved in the expression of the MAOA gene, therefore imbalances in the relation between circadian rhythms and neurotransmitter degradation may contribute towards an increased BD susceptibility (Geoffroy, 2018). Effects of Li on FAR2 (fatty acyl CoA reductase 2) methylation and insulin resistance was done in another paper, although the main focus of the research was on second generation antipsychotics (Burghardt et al, 2016). Only 25% of the 72 subjects included were on Li monotherapy, so lack of association between FAR2 methylation levels and Li treatment could be a consequence of the small sample size.…”