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

Understanding antidepressant mechanisms could help design more effective and tolerated treatments.

Identify DNA methylation (DNAm) changes associated with antidepressant exposure.

Case-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.

Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR.

Participants with DNAm data and self-report/prescription derived antidepressant exposure.

Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N _exposed = 661, N _unexposed = 9,575) alongside MBD-Seq in NESDA (N _exposed = 398, N _unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions.

The self-report MWAS (N = 16,536, N _exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N _exposed = 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, p _self-report = 9.3x10 ^-13 , p _prescription = 6.1x10 ^-3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p _adj = 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 (N _studies = 9, N = 10,236, N _exposed = 661, f3 = 0.196, p < 1x10 ^-4 ).

Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments.

Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In 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. Meaning: Antidepressant 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.