Research paperA MIR4646 associated methylation locus is hypomethylated in adolescent depression

- First study investigating genome-wide DNA methylation shifts in MDD in a population-based cohort of adolescents.
- A MIR4646 associated methylation locus is identified and confirmed to be hypomethylated in adolescent MDD.
- The methylation locus was also hypomethylated in glial cells extracted post mortem from the frontal cortex of adults with MDD.
- In a group of healthy controls, cg04102384 methylation levels are inversely correlated with gene expression of MIR4646-3p.
- Target gene prediction revealed involvement of MIR4646-3p in processes related to omega-3 fatty acids.

BackgroundStudies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression.MethodsWe present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n=93) and validation data set 1 (n=78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n=58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers.ResultsThe methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p<10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p<0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p<0.05).LimitationsMIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements.ConclusionWe identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression.