Author(s): Christina A Castellani aff1 , Melkaye G Melka aff1 , Eric J Diehl aff1 , Benjamin I Laufer aff1 , Richard L O'Reilly aff2 , Shiva M Singh [*] aff1 aff2
antipsychotics; DNA methylation; environment; epigenomics; exposure; mental disorders; monozygotic twins; olanzapine; psychosis
It is now apparent that the manifestation of the genetic code into psychiatric phenotypes including mental disorders is not determined solely by DNA sequence [1,2 ]. The causation of psychiatric disorders involves complex interactions involving chromatin, where epigenetic signals superimpose a regulatory role. In fact, it has been suggested that the missing heritability seen in neuropsychiatric disorders could be due in part to the effect of epigenetic patterning [1,2 ]. This perspective suggests that the epigenome is in a dynamic state influenced by both deterministic as well as stochastic processes. This complexity also makes it difficult to tease apart the underlying factors that contribute to its state at any given time [3 ]. It represents a major challenge for future studies. For now, and for a variety of reasons, this research is accentuated by studies on epigenetic processes involving DNA methylation. DNA methylation in mammals involves the modification of cytosine to methylated cytosine (or its equivalent) in the genome. The phenomenon is sequence specific and needed for the proper functioning of the genome. DNA methylation provides regulatory roles in cellular functioning via regulation of gene transcription [4 ], genomic imprinting [5 ], gene splicing [6 ] and chromatin structure and stability [7 ]. Indeed, any aberration from normal patterns of methylation may cause abnormal cellular functioning including disease phenotypes [8 ]. Potentially, DNA methylation profiles can be altered by various factors including seasonal, social and environmental factors as well as chemicals and drugs [9,10 ]. This dynamic property may help to further the understanding of disease processes including mechanisms of actions of drugs that are used to treat disease. For example, it remains unknown how antipsychotic drugs control emotional and behavioral symptoms. The most accepted explanation is that antipsychotics have their own receptor-binding profiles, pharmacologic profiles and mechanisms of action [11-14 ]. Often, the treatment protocol involves 'testing and trying' toward finding a suitable drug and its appropriate dose for each patient. Some patients fail to respond to one antipsychotic but subsequently show a robust response to a different drug despite the fact that both block the D2 receptor, which is believed to be their mechanism of action [15 ]. Also, adverse effects of antipsychotic drugs vary greatly across patients [16 ]. Further, the delayed response of antipsychotics [17 ] and the associated variable metabolic side effects remain poorly understood [18-20 ]. It is however understood that drugs used to treat psychiatric disorders may cause epigenetic changes in the genome [21,22 ]. These changes have been identified in patients with psychosis that were on antipsychotic medication as compared with controls who were not on any medication. In fact, there have been a number of reports on epigenetic profile differences in psychosis patients, but the role of epigenetic changes in the causation of psychosis...