Elucidating the role of DNA methylation in bipolar disorder in the context of suicide attempt and lithium use

DNA methylation (DNAm) is a dynamic process characterized by the addition to a methyl group to the 5' carbon of a cytosine. Changes in DNAm have been associated with various psychiatric diseases. One such psychiatric disorder associated with differential DNAm is bipolar disorder (BD).

In this thesis, DNAm is explored in BD in the context of history of suicide attempt (SA) and lithium use. While individuals with BD tend to have an approximately 10-year shorter lifespan than the general population that is not explained by suicide death. By investigating DNAm in cytosine-guanine dinucleotides, or CpG sites, associated with aging, we explore the biological (epigenetic) aging of individuals with BD and history of SA. These individuals have a faster pace of aging and accelerated epigenetic aging compared to controls and BD without SA. The investigation of the candidate gene ARHGEF38 in SA highlights the importance of looking at both genetic and epigenetic data when assessing differences between phenotypes.

There are differentially methylated probes associated with BD and lithium use compared to those who do not use lithium. These CpGs implicate lithium use in inflammatory and immune response as well as the Wnt signaling pathway. We then treated human skin-derived fibroblasts with lithium chloride to identify changes in global methylation to show that fibroblasts from individuals using and not using lithium respond differently to lithium treatment.

Together, these findings help better understand BD and identify potential biomarkers to identify lithium use and SA, as well as therapeutic targets.