Effects of the epigenome on the pathogenesis of schizophrenia

Schizophrenia is a debilitating psychiatric disorder, in which the affected patient experiences hampered ability to perceive reality. It is among the most researched and least understood mental diagnoses, particularly because its pathogenesis lies at the intersection of polygenic heritable traits and diverse environmental stimuli. Kimberly Shorter and Brooke Miller, from the McKnight Brain Institute and Depts. of Psychiatry and Medicine at the University of Florida, recently reviewed current understanding of epigenetic influence on the schizophrenic phenotype. As it turns out, the neurochemical situation behind schizophrenia is still largely unknown, with evidence for the role of the neurotransmitter dopamine based on the efficacy of antipsychotic drugs that target it; however, genome-wide association studies show little difference between dopamine-related genes in schizophrenic (SCZ) and non-SCZ individuals. The search for differences must then turn to the epigenome: the collective regulation and de-regulation of select regions of DNA, responsible for the same species-wide genome presenting itself differently in 7 billion people worldwide.

"Epigenetic modifications" may entail methylation and demethylation of strand of DNA, respectively preventing or allowing transcription of genes into RNA/protein; histone modifications, such as acetylation; non-coding RNA; and coiling/super-coiling of chromatin, i.e. how tightly packed the cell stores various stretches of its DNA. Genes related to schizophrenia include brain-derived neurotrophic factor, glucocorticoid receptor, glutamate decarboxylase 1, and reelin---in SCZ patients, all four of these genes are hypermethylated and heavily down-regulated. Interestingly enough, some of these genes have also shown association with substance dependency, autism, bipolar disorder, and Alzheimer's disease. So while the connection to neural function is clear, this case highlights the frustrating truth that many symptomatically different brain disorders seem to stem from overlapping causes. Another gene, ST6GALNAC1, associated with stress-activated kinase signaling, is severely de-methylated in SCZ post-mortem brain tissue, resulting in overexpression of the gene in patients.

Histone acetylation, an epigenetic mechanism that causes DNA/chromatin to un-coil and loosen in structure, allowing transcription, is also implicated by the pharmacology of schizophrenia treatment. A common treatment for both SCZ and bipolar disorder (BPD) is the drug valproic acid (VPA); VPA functions to inhibit the enzymes that de-acetylate histones, thereby maintaining acetylation and the expression of genes. One histone deacetylase in particular, HDAC1, is overexpressed in SCZ patients and leads to overexpression of genes particularly located around histone 3. For this reason, Shorter and Miller propose investigation of more specific inhibitors that target only the HDAC's associated with schizophrenia; this way, the side effects of "off-targeting" by drugs such as valproic acid may be reduced.

The review is highly informative and provides exciting insights on the use of epigenome studies to better human health---in time, our understanding of epigenetic diversity and phenomena may be able to lessen the suffering and improve the lives of many who struggle with mental health.

Fig. 1 - Self-portrait by Craig Finn, a schizophrenic man (PLoS Med, 2005)