Investigating the Relationship Between DNA Methylation, Genetic Variation, and Suicide Attempt in Bipolar Disorder.

Abstract

Objective: Individuals with bipolar disorder are at increased risk for suicide, and this can be influenced by a range of biological, clinical, and environmental risk factors. Biological components associated with suicide include DNA modifications that lead to changes in gene expression. Common genetic variation and DNA methylation changes are some of the most frequent types of DNA findings associated with an increased risk of suicide attempt. Importantly, the interplay between genetic predisposition and DNA methylation patterns is becoming more prevalent in genetic studies. We hypothesized that DNA methylation patterns in specific loci already genetically associated with suicide would be altered in individuals with bipolar disorder and a history of suicide attempt.

Method: To test this hypothesis, we searched the literature to identify common genetic variants (N = 34) previously associated with suicidal thoughts and behaviors in individuals with bipolar disorder. We then created a customized sequencing panel that covered our chosen genomic loci. We profiled DNA methylation patterns from blood samples collected from bipolar disorder participants with a history of suicide attempt (N = 55) and without (N = 51).

Results: We identified seven differentially methylated CpG sites and five differentially methylated regions between the two groups. Additionally, we found that DNA methylation changes in MIF and CACNA1C were associated with lethality or number of suicide attempts. Finally, we identified three meQTLs in SIRT1, IMPA2, and INPP1.

Conclusions: This study illustrates that DNA methylation is altered in individuals with bipolar disorder and a history of suicide attempts in regions known to harbor suicide-related variants.