Objective: 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.
Method: 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.
Results: 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.
Conclusions: 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.
Keywords: ARHGEF38; Epigenetics; bipolar disorder; genetics; suicide attempt.
DNA methylation is a dynamic modification to DNA that changes throughout our lifetime due to a variety of extrinsic and intrinsic factors. This study aimed to investigate whether DNA methylation patterns in a gene previously associated with suicide death (ARHGEF38) was associated with a history of suicide attempts in individuals with bipolar disorder. To do this, we extracted DNA from whole blood samples from individuals with bipolar disorder (with and without a history of suicide attempts), and a control group without bipolar disorder. Using a targeted technique called pyrosequencing, we examined the methylation levels of three specific CpG sites within the ARHGEF38 gene.This study found no significant differences in methylation levels between the groups at the three CpG sites analyzed. However, we did identify genetic variation close to the CpG sites that were associated with the identified DNA methylation patterns.This study did not replicate the previous finding that linked ARHGEF38 to suicide death. Several differences between the previous study and this one may have influenced the negative finding, including the suicide phenotype, the tissue type, and the presence of genetic variation. This study is still notable as it highlights the complex interplay between genetic variants and DNA methylation patterns in epigenetic research.