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Epigenetics in psychiatric disorders: A guide for beginners

12 March 2010
By Sally Marlow
Sally Marlow is a postgraduate student at the Institute of Psychiatry, where her research topics include the role of epigenetics in alcohol dependence
Appeared in BioNews 549
Mental health is a huge global concern, with one in four people experiencing some form of mental health problem at some point in their lives (1). Psychiatric disorders are sometimes difficult to study, as they are diagnosed on the basis of observed behaviours. Research is further complicated in that some chronic psychiatric disorders follow an almost circular disease course, where certain periods and events in the lifespan are particularly associated with onset, remission and relapse.

Adding to this complexity is the role played by genes. We know from family, twin and adoption studies that there is a substantial genetic component in disorders such as schizophrenia, bipolar disorder and major depressive disorder. Some headway has been made in the search to identify genetic variants underlying psychiatric disorders (2). This research is not straightforward, as it is rare that just one genetic variant is necessary or sufficient for one disorder. Also certain genes seem to play a role in multiple disorders.

Genetic vulnerability, whilst important, is clearly not the whole story. Identical twins, who are in effect genetic clones, show different rates of concordance in psychiatric disorders. This suggests that the environment must also play a role in determining why one twin should get a disorder, but not the other (3). What is not fully understood is the nature of the relationship between genes and the environment. It appears that the environment may influence behaviour by altering the expression of genes (think of this as genes being switched on), but we do not yet know exactly how this is controlled.

Epigenetics may hold the key to tackling these issues. Epigenetics is the study of changes in gene activity that occur without changes to the sequence of DNA. Epigenetic processes are the chemical processes that can be influenced by environmental factors to switch genes on, or to switch them off. The most widely studied and stable epigenetic process is DNA methylation, when a methyl group comprised of one carbon atom attached to three hydrogen atoms is added to the DNA. Also important are various modifications to histone (a type of simple protein present in cell nuclei) which alter the way that the DNA is packaged. Crucially, these epigenetic processes are dynamic and reversible.

Although this is a relatively new area of research, both animal model and human studies are coming thick and fast. There are encouraging findings in areas such as schizophrenia (4). Epigenetic differences have also been found in post-mortem brains of people with major depressive disorder who commit suicide (5) - suicide victims' brains had methylation rates almost ten times higher than controls across certain regions of the genome. Even more intriguingly, suicide victims who had suffered child abuse had different DNA methylation profiles at a gene associated with the stress response when compared with suicides who had not suffered abuse (6), providing a clear link between an environmental trigger and an epigenetic response. Recent studies also suggest that DNA methylation at certain neurotransmitter gene sites may be involved in alcohol dependence (7). Epigenetic mechanisms have even been found to be at work in eating disorders (8).

For a field which is still in its infancy, these findings are extremely promising, especially considering the dynamic and reversible nature of epigenetic processes. If epigenetic disruption is implicated in these disorders, perhaps we can reverse that disruption. Indeed existing psychiatric treatment may already confer epigenetic changes. For example, therapeutic interventions for depression which have been shown to have lasting epigenetic effects include electroconvulsive therapy and the antidepressant imipramine, and certain antipsychotic medications have been associated with lower DNA methylation in patients with schizophrenia (9).

Looking to the future, as the technologies involved in epigenetic profiling continue to evolve, we can now begin to identify epigenetic processes which perform a function between specific environmental risk factors and changes in gene expression. Those environmental factors may occur in the womb or in the outside world. They could include psychosocial influences as well as exposure to food, drugs and toxins, for example. It is often claimed that preliminary scientific findings have enormous transformational potential. In the case of the role of epigenetic processes in psychiatric disorders, that claim might just prove true. Epigenetic findings could influence how we design drugs, the routes we use to administer them to their biological targets, and dosing levels. They could also inform how we design psychosocial therapies. All of this could be important not only for treatment of psychiatric disorders, but also for their prevention, and provide therapeutic benefit at both a population level and an individual level.

1) The Future Vision Coalition: A future vision from mental health (2009)
Mind |  12 March 2010
2) R Plomin, JC DeFries, GE McClearn & P McGuffin. Behavioural Genetics
New York: Worth Publishers |  22 February 2008
3) MF Fraga, E Ballestar and MF Pz et al., Epigenetic differences arise during the lifetime of monozygotic twins
Proc Natl Acad Sci USA. 102: 10604 – 10609 |  2008
4) J Mill, T Tang, Z Kaminsky et al. Epigenomic profiling reveals DNA methylation changes associated with major psychosis
Am J Hum Genet. 82 (3): 696-711 |  2008
5) MO Poulter, L Du, ICG Weaver, M Palkovits, G Faludi, Z Merali, M Szyf, H Anisman.  GABA A Receptor Promoter Hypermethylation in Suicide Brains:  Implications for the Involvement of Epigenetic Processes
Biol Psychiatry. 64: 645 – 652 |  2008
6) PO McGowan, A Sasaki, AC D'Alessio, S Dymov, B Labonté, M Szyf, G Turecki, MJ Meaney.  Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.
Nat Neurosci. 12(3):342-8 |  2009
7) RA Philibert, TD Gunter , SR Beach, GH Brody & A Madan. MAOA methylation is associated with nicotine and alcohol dependence in women.
Am J Med Genet B Neruopsychiatr Genet. 147 B: 565 – 70 |  2008
8) H Frieling, KD Romer, S Scholz et al.  Epigenetic dysregualtion of dopaminergic genes in eating disorders.
Int J Eating Disorders. epub ahead of print |  2009
9) S Docherty & J Mill. Epigenetic mechanisms as mediators of environmental risks for psychiatric disorders.
Psychiatry. 7 (12): 500 – 506. |  2008
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