SNP-associated differential methylation in ARHGEF38: insights into genetic-epigenetic interactions

Associations have been seen between suicide and differential DNA methylation, with one study showing significant hypomethylation of ARHGEF38 in individuals with bipolar disorder who died by suicide. Our objective was to explore ARHGEF38 methylation in individuals with bipolar disorder and a history of suicide attempt.

With pyrosequencing, we looked at the previously identified region of interest in ARHGEF38. We investigated the methylation levels of three CpG sites in 47 individuals with bipolar disorder and a history of suicide attempt, 47 individuals with bipolar disorder without a history of suicide attempt, and 47 non-bipolar disorder controls.

None of the CpG sites measured had an association between groups, although there were distinct clusters of differential methylation in each group. Applying genotypes of SNPs found in the region of interest, rs2121558 and rs1447093, these clusters showed stepwise methylation at each CpG site, regardless of phenotype.

In this small sample size study, differential methylation in ARHGEF38 was not associated with history of suicide attempt, failing to replicate findings from a related outcome, suicide death. However, we did provide evidence of SNP and DNA methylation interplay in this region. This highlights the relevance of considering genetics when interrogating epigenetic mechanisms.