Marco P. Boks, M.D., Ph.D., Rudolf Magnus Institute of Neuroscience, 2009 NARSAD Young Investigator Grantee: "Methylation as an Epigenetic Cause of Schizophrenia"

My idea is not entirely new and not entirely original. That said; there are also not many people pursuing this idea as far as I know. Probably because there are just too many uncertainties and we first need to learn much more about the basic sciences. I am talking about epigenetic treatment. I think it is possible (indeed likely) that epigenetic mechanisms play an important role in the development of bipolar disorder and schizophrenia. The intriguing thing to me is that such epigenetic mechanisms are (unlike the genetic background of people) susceptible to manipulation with drugs or diet. In our recent review: “The current status and future prospects of epigenetic psychopharmacology” we point out that many psychiatric drugs exert influence on the epigenome, with valproic acid (depakote) being the best known example. Moreover, several compounds with epigenetic properties show some promise as future drugs.

Epigenetics is the study of how genes are silenced or activated by mechanisms that were identified almost a century ago. The best known epigenetic mechanisms are DNA methylation, histone acetylation and microRNA’s but there are many, many more. It is easy to see why such mechanisms are relevant; when one has susceptibility genes for bipolar disorder, but they are silenced, clearly they will not be bothersome. Inversely, when protective genes are silenced, one is at risk. Compelling evidence now suggest that epigenetic mechanisms (particularly DNA methylation) are involved in the risk for developing bipolar disorder and schizophrenia.

The challenge for such studies is to deal with the influence of genotype, medication, and tissue type. With the support of the Brain & Behavior Research Foundation and a NARSAD Grant, we measured DNA methylation at over 27,000 loci in whole blood samples from monozygotic twin pairs (N=26 pairs) discordant for bipolar disorder. This was an international, collaborative effort with:

• London-based team: Dr. Jonathan Mill, 2008 NARSAD Young Investigator Grantee: "Linking Adolescent Cannabis Exposure to Schizophrenia: The Role of DNA Methylation" and Dr. Robin MacGregor Murray, 1999 NARSAD Distinguished Investigator Grantee: "Cognitive Correlates of Hypofrontality in Monozygotic Twins Discordant for Schizophrenia:  A Functional Imaging (fMRI) Investigation”
• a team in Utrecht, the Netherlands: Drs. Hilleke Hulshof-Poll and René Kahn
• Los Angeles-based team: Dr. Roel A. Ophoff, 2002 NARSAD Young Investigator Grantee: "Implications of small chromosome 8p inversions neuropsychiatric traits" and 2008 NARSAD Independent Investigator Grantee: "The Role of Epigenetic DNA Methylation and Schizophrenia Susceptibility"

We found plausible evidence that DNA hypomethylation at a particular locus is associated with bipolar disorder, independent from genetic background, age and gender. We found supportive results in the brain and analysis of brain volume. This is a first step in what is sure to be a long road of further discoveries, leading to better understanding and treatment of bipolar disorder and schizophrenia.  We are hopeful that new targeted epigenetic therapies for bipolar disorder and schizophrenia will be possible with further research and discoveries.