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

ImportanceUnderstanding 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 to DGUOK-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 PointsO_ST_ABSQuestionC_ST_ABSIs 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 to KANK1 and DGUOK-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 at KANK1 and DGUOK-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.