Epigenetic gene regulation may play role in psychiatric disorders

Schizophrenia, bipolar disorder and other psychiatric disorders are complex illnesses in which neural circuit structure and function are altered. Although inheritance plays an important role in the etiology of these conditions, the 50 to 70 percent concordance rates among identical twins indicate that environmental factors also also involved. Evidence increasingly suggests that these changes are maintained by epigenetic modifications, especially DNA methylation, according to Marin Veldic, M.D., a psychiatrist and epigenetics researcher at Mayo Clinic's campus in Rochester, Minnesota.

DNA methylation — the addition of a methyl group on the cytosine of CpG dinucleotides — may alter gene expression by restricting access of transcription factors to promoter regions or changing mRNA processing. Although these alterations don't change the genetic code, they are long lasting and may be heritable.

Methylation studies

Most of what is known about the role of DNA methylation in schizophrenia and other psychiatric disorders is based on studies of postmortem brain tissue, peripheral blood or both. Dr. Veldic co-authored a study published in Schizophrenia Research in 2009 that found overexpression of both DNA-methyltransferase-1 (DNMT-1) and DNMT3a mRNA — but not DNMT3b — in cortical GABAergic neurons in patients with schizophrenia, leading to promoter hypermethylation. A twofold increase of DNMT-1 and DNMT3a mRNA was also observed in peripheral blood lymphocytes.

Conversely, a 2013 study published in Alcoholism: Clinical and Experimental Research found that the increase in DNMT-1 was reversed in patients with schizophrenia or bipolar disorder who had a history of excessive alcohol use. Dr. Veldic suggests that alcohol addiction may represent a form of acquired comorbidity for some patients. More recently, large methylome- and epigenome-wide association studies have used next-generation sequencing to identify schizophrenia methylation biomarkers in blood. A study published in JAMA Psychiatry in 2014 reported alterations in methylation of genes related to hypoxia and infection, two risk factors in early life associated with later schizophrenia. And a 2016 epigenome-wide association study, also in JAMA Psychiatry, identified 172 replicated sites of altered methylation in patients with schizophrenia.

Dr. Veldic says the growing number of high-quality methylation studies can advance mental health research in several important ways. For example, it may be possible to identify disease subtypes using easily obtained blood biomarkers that would allow for earlier or more precise diagnosis. Methylation studies can also generate hypotheses about disease mechanisms. And methylation sites in the brain that are reflected in peripheral blood may help confirm that environmental factors can affect methylation in many areas, not just brain tissue.

"The whole field is growing enormously," Dr. Veldic says. "When I was starting out more than 15 years ago, there were just a few papers — now there are hundreds, and this research will have a significant clinical and translational impact."

For more information

Zhubi A, et al. An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes. Schizophrenia Research. 2009;111:115.

Guidotti A, et al. DNA methylation/demethylation network expression in psychotic patients with a history of alcohol abuse. Alcoholism: Clinical and Experimental Research. 2013; 37:417.

Aberg KA, et al. Methylome-wide association study of schizophrenia: Identifying blood biomarker signatures of environmental insults. JAMA Psychiatry. 2014;71:255.

Montano C, et al. Association of DNA methylation differences with schizophrenia in an epigenome-wide association study. JAMA Psychiatry. 2016;73:506.