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It is thought that the insulin resistance resulting from the use of <jats:styled-content style=\"fixed-case\">AAP<\/jats:styled-content>s may be associated with changes in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation. We aimed to identify and validate a candidate gene associated with <jats:styled-content style=\"fixed-case\">AAP<\/jats:styled-content>\u2010induced insulin resistance by using a multi\u2010step approach that included an epigenome\u2010wide association study (<jats:styled-content style=\"fixed-case\">EWAS<\/jats:styled-content>) and validation with site\u2010specific methylation and metabolomics data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Subjects with bipolar disorder treated with <jats:styled-content style=\"fixed-case\">AAP<\/jats:styled-content>s or lithium monotherapy were recruited for a cross\u2010sectional visit to analyze peripheral blood <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation and insulin resistance. Epigenome\u2010wide <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation was analyzed in a discovery sample (<jats:italic>n<\/jats:italic>\u00a0=\u00a048) using the Illumina 450K BeadChip. Validation analyses of the epigenome\u2010wide findings occurred in a separate sample (<jats:italic>n<\/jats:italic>\u00a0=\u00a072) using site\u2010specific 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 <jats:styled-content style=\"fixed-case\">AAP<\/jats:styled-content>\u2010induced insulin resistance occurs through changes in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A differentially methylated probe associated with insulin resistance was discovered and validated in the fatty acyl CoA reductase 2 (<jats:italic><jats:styled-content style=\"fixed-case\">FAR<\/jats:styled-content>2<\/jats:italic>) gene of chromosome 12. Functional associations of this <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation site with untargeted phospholipid\u2010related metabolites were also detected. Our results identified a mediating effect of this <jats:italic><jats:styled-content style=\"fixed-case\">FAR<\/jats:styled-content>2<\/jats:italic> methylation site on <jats:styled-content style=\"fixed-case\">AAP<\/jats:styled-content>\u2010induced insulin resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Going forward, prospective, longitudinal studies assessing comprehensive changes in <jats:italic><jats:styled-content style=\"fixed-case\">FAR<\/jats:styled-content>2<\/jats:italic> <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation, expression, and lipid metabolism before and after <jats:styled-content style=\"fixed-case\">AAP<\/jats:styled-content> treatment are required to assess its potential role in the development of insulin resistance.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bdi.12422","type":"journal-article","created":{"date-parts":[[2016,8,20]],"date-time":"2016-08-20T07:08:47Z","timestamp":1471676927000},"page":"423-432","source":"Crossref","is-referenced-by-count":33,"title":["Gene\u2010specific <scp>DNA<\/scp> methylation may mediate atypical antipsychotic\u2010induced insulin resistance"],"prefix":"10.1111","volume":"18","author":[{"given":"Kyle J","family":"Burghardt","sequence":"first","affiliation":[{"name":"Department of Pharmacy Practice Wayne State University Eugene Applebaum College of Pharmacy and Health Sciences  Detroit MI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacyln M","family":"Goodrich","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences University of Michigan School of Public Health  Ann Arbor MI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana C","family":"Dolinoy","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences University of Michigan School of Public Health  Ann Arbor MI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vicki L","family":"Ellingrod","sequence":"additional","affiliation":[{"name":"Department of Clinical Social and Administrative Sciences University of Michigan College of Pharmacy  Ann Arbor MI USA"},{"name":"Department of Psychiatry University of Michigan School of Medicine  Ann Arbor MI 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