Epigenetics and bipolar disorder: New opportunities and challenges

Abstract

Despite significant effort, understanding of the molecular causes and mechanisms of bipolar disorder (BD) remains a major challenge. Numerous molecular genetic linkage and association studies have been conducted over the last two decades; however, the data are quite inconsistent or even controversial. This article develops an argument that molecular studies of BD would benefit significantly from adding an epigenetic (epiG) perspective. EpiG factors refer to modifications of DNA and chromatin that "orchestrate" the activity of the genome, including regulation of gene expression. EpiG mechanisms are consistent with various non-Mendelian features of BD such as the relatively high degree of discordance in monozygotic (MZ) twins, the critical age group for susceptibility to the disease, clinical differences in males and females, and fluctuation of the disease course, including interchanges of manic and depressive phases, among others. Apart from the phenomenological consistency, molecular epiG peculiarities may shed new light on the understanding of controversial molecular genetic findings. The relevance of epigenetics for the molecular studies of BD is demonstrated using the examples of genetic studies of BD on chromosome 11p and the X chromosome. A spectrum of epiG mechanisms such as genomic imprinting, tissue-specific effects, paramutagenesis, and epiG polymorphism, as well as epiG regulation of X chromosome inactivation, is introduced. All this serves the goal of demonstrating that epiG factors cannot be ignored anymore in complex phenotypes such as BD, and systematic large-scale epiG studies of BD have to be initiated.

Dense SNP association study for bipolar I disorder on chromosome 18p11 suggests two loci with excess paternal transmission

“…5,12 Parent-of-origin effects imply an epigenetic mechanism of inheritance and may be a compelling hypothesis to explain complex genetic disorders such as bipolar disorder. [44][45][46] The paternal allele sharing in the Fallin et al 9 linkage study is described by microsatellite markers D18S59 and D18S63; the two loci (four SNPs) with putative parent-of-origin effects in this study map between these two markers and is therefore consistent with previous results. These loci confer substantial risk for bipolar disorder (fourfold and sixfold respectively, relative to maternal transmission).…”

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

“…49 Especially, POE in the transmission of bipolar disorder suggests the role of genomic imprinting. In bipolar disorder, several reports suggested the involvement of POE.…”

Valproate and Amitriptyline Exert Common and Divergent Influences on Global and Gene Promoter-Specific Chromatin Modifications in Rat Primary Astrocytes

“…In humans, there is mounting evidence that epigenetic mechanisms are involved in the pathophysiology of stress-related disorders, including unipolar and bipolar depression (Mill and Petronis, 2007;Petronis, 2003). Postmortem studies of suicide victims with a history of depression or childhood abuse showed differential expression of DNMT subtypes (Poulter et al, 2008) and promoter-wide hypermethylation of ribosomal RNA gene promoters , respectively.…”