Unstable genes unstable mind: beyond the central dogma of molecular biology

Schizophrenia has a polygenic mode of inheritance and an estimated heritability of over 80%, but success in understanding its genetic underpinnings to date has been modest. Unlike in trinucleotide neurodegenerative disorders, the phenomenon of genetic anticipation observed in schizophrenia or bipolar disorder has not been explained. For the first time, we provide a plausible molecular explanation of genetic anticipation and pathophysiology of schizophrenia, at least in part, with supporting evidence. We postulate that abnormally increased numbers of CAG repeats in many genes being expressed in the brain, coding for glutamine, cumulatively press for higher demand of glutamine in the respective brain cells, resulting in a metabolic crisis and dysregulation of the glutamate-glutamine cycle. This can adversely affect the functioning of both glutamate and GABA receptors, which are known to be involved in psychosis, and may also affect glutathione levels, increasing oxidative stress. The resulting psychosis (gain in function), originating from unstable genes, is described as an effect “beyond the central dogma of molecular biology”. The hypothesis explains genetic anticipation, as further expansions in subsequent generations may result in increased severity and earlier occurrence. Many other well described findings provide proof of concept. This is a testable hypothesis, does not deny any known facts and opens up new avenues of research.