Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study

Abstract

AbstractImportanceUnderstanding antidepressant mechanisms could help design more effective and tolerated treatments.ObjectiveIdentify DNA methylation (DNAm) changes associated with antidepressant exposure.DesignCase-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS.SettingCohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR.ParticipantsParticipants with DNAm data and self-report/prescription derived antidepressant exposure.Main Outcome(s) and Measure(s)Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, Nexposed= 661, Nunexposed= 9,575) alongside MBD-Seq in NESDA (Nexposed= 398, Nunexposed= 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions.ResultsThe self-report MWAS (N = 16,536, Nexposed= 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, Nexposed= 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10-8), respectively. The top locus was cg26277237 (KANK1,pself-report=9.3x10-13, pprescription= 6.1x10-3). The self-report MWAS found a differentially methylated region, mapping toDGUOK-AS1 (padj= 5.0x10-3) alongside significant enrichment for genes expressed in the amygdala, the “synaptic vesicle membrane” gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (Nstudies= 9, N = 10,236, Nexposed= 661, f3 = 0.196, p < 1x10-4).Conclusions and RelevanceAntidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments.3 Key PointsQuestionIs antidepressant exposure associated with differential whole blood DNA methylation?FindingsIn this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping toKANK1andDGUOK-AS1.A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10-4) in a meta-analysis of external datasets.MeaningAntidepressant exposure is associated with hypermethylation atKANK1andDGUOK-AS1, which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.