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

AI Article Synopsis

  • Understanding how antidepressants work at a molecular level can lead to better therapies that people tolerate well.
  • The study analyzed DNA methylation changes linked to antidepressant use across multiple cohorts, using blood samples and data collected between 2006 and 2011.
  • Results showed specific DNA regions with increased methylation in individuals using antidepressants, with findings suggesting connections to brain-related genes and providing insights for further research on treatment effectiveness.

Article Abstract

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

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

Design: 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.

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

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

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

Results: The self-report MWAS (N = 16,536, N = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 ), respectively. The top locus was cg26277237 ( p 9.3x10 , p = 6.1x10 ). The self-report MWAS found a differentially methylated region, mapping to p = 5.0x10 ) 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 = 9, N = 10,236, N = 661, f3 = 0.196, p < 1x10 ).

Conclusions And Relevance: Antidepressant 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 Points: Is antidepressant exposure associated with differential whole blood DNA methylation? In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to and 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 ) in a meta-analysis of external datasets. Antidepressant exposure is associated with hypermethylation at and , 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092700PMC
http://dx.doi.org/10.1101/2024.05.01.24306640DOI Listing

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