Epigenetics of Bipolar Disorder

Bipolar disorder is an episodic illness with periods of depression alternating with periods of elevated mood. Its fluctuating course and the evidence that stress can play a triggering role in the illness suggest the possibility of an epigenetic component to pathogenesis and pathophysiology. We review early evidence from parent-of-origin specific inheritance studies and linkage studies that raised the possibility of genomic imprinting in bipolar disorder. We then review molecular data on DNA methylation and histone modifications in bipolar disorder at the level of single genes and genome wide. Finally, we examine the impact of stress and of mood stabilizing medications on epigenetic variation. No definitive results have yet been published that clearly demonstrate a role for epigenetic variation in bipolar disorder etiology or pathophysiology. Potentially fruitful future directions for study in this area include examining DNA methylation from the same patients in different phases of the illness, from patients before and after successful treatment with medications such as sodium valproate, from patients before and after major stressors, and from animal models of stress-induced mood disorder. Although the epigenome-wide approach can lead to hypothesis-free discovery of newly implicated genes, focused studies of single genes implicated by other approaches such as genome-wide association studies will allow for much greater depth of investigation (i.e., across the entire gene) in different tissue and cell types and at varying developmental stages.