Paradox of schizophrenia genetics: is a paradigm shift occurring?

Abstract

Background: Genetic research of schizophrenia (SCZ) based on the nuclear genome model (NGM) has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, the current situation of the molecular genetics of SCZ seems disappointing or rather perplexing. Furthermore, a prominent discrepancy between persistence of the disease at a relatively high prevalence and a low reproductive fitness of patients creates a paradox. Heterozygote advantage works to sustain the frequency of a putative susceptibility gene in the mitochondrial genome model (MGM) but not in the NGM.

Methods: We deduced a criterion that every nuclear susceptibility gene for SCZ should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. SCZ-associated variants listed in the top 45 in the SZGene Database (the version of the 23rd December, 2011) were selected, and the distribution of the genes that could meet or do not meet the criterion was surveyed.

Results: 19 SCZ-associated variants that do not meet the criterion are located outside the regions where the SCZ-associated variants that could meet the criterion are located. Since a SCZ-associated variant that does not meet the criterion cannot be a susceptibility gene, but instead must be a protective gene, it should be linked to a susceptibility gene in the NGM, which is contrary to these results. On the other hand, every protective gene on any chromosome can be associated with SCZ in the MGM. Based on the MGM we propose a new hypothesis that assumes brain-specific antioxidant defenses in which trans-synaptic activations of dopamine- and N-methyl-d-aspartate-receptors are involved. Most of the ten predictions of this hypothesis seem to accord with the major epidemiological facts and the results of association studies to date.

Conclusion: The central paradox of SCZ genetics and the results of association studies to date argue against the NGM, and in its place the MGM is emerging as a viable option to account for genomic and pathophysiological research findings involving SCZ.

Figure 1

Proposed pathophysiology of schizophrenia. Mitochondrial dysfunction (MD), through imbalance of ROS production and removal, raises ROS emission, causing a strong intracellular OS. Disturbed OXPHOS and enhanced OS in predisposed individuals may cause various pathogenic alterations such as genomic instability, aberrations in neuromuscular development, brain dysfunction, and apoptosis. On the other hand, enhanced OS and secondarily induced alteration of redox coenzyme homeostasis may cause enhanced CS. It is assumed that the brain has the third class of antioxidant defenses in which neurotransmissions are involved, and that trans-synaptic activation of NMDA-R as well as DA-R may occur, through unknown pre-synaptic redox regulation mechanisms, as an adaptive response to OS which could not be suppressed by the class I (non-enzymatic) and II (enzymatic) defenses. Failure to suppress OS by those three classes of antioxidant defenses may lead to persistent strong OS and, through suppressing the expression of inhibitory interneurons, may cause prolonged excessive glutamate and/or DA release, leading to excitation toxicity (ET) and additional deterioration of the brain function.