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Gene‐specific DNA methylation may mediate atypical antipsychotic‐induced insulin resistance
Author(s) -
Burghardt Kyle J,
Goodrich Jacyln M,
Dolinoy Dana C,
Ellingrod Vicki L
Publication year - 2016
Publication title -
bipolar disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.285
H-Index - 129
eISSN - 1399-5618
pISSN - 1398-5647
DOI - 10.1111/bdi.12422
Subject(s) - dna methylation , insulin resistance , methylation , epigenetics , biology , epigenome , cpg site , differentially methylated regions , genetics , insulin , bioinformatics , gene , medicine , endocrinology , gene expression
Objectives Atypical antipsychotics ( AAP s) carry a significant risk of cardiometabolic side effects, including insulin resistance. It is thought that the insulin resistance resulting from the use of AAP s 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 Subjects with bipolar disorder treated with AAP s 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 ( FAR 2 ) gene of chromosome 12. Functional associations of this DNA methylation site with untargeted phospholipid‐related metabolites were also detected. Our results identified a mediating effect of this FAR 2 methylation site on AAP ‐induced insulin resistance. Conclusions Going forward, prospective, longitudinal studies assessing comprehensive changes in FAR 2 DNA methylation, expression, and lipid metabolism before and after AAP treatment are required to assess its potential role in the development of insulin resistance.