Abstract
BackgroundGenetic 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.MethodsWe 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.Results19 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.ConclusionThe 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.
Highlights
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
Heterozygote advantage does not seem to work in the NGM. It works in the mitochondrial genome model (MGM) because Mitochondrial DNA (mtDNA) is transmitted to the generation only through females
Database could meet the criterion under the assumption that the mutation rates at those loci are near the upper limit on the autosomes and the X chromosome (Tables 1 and 2)
Summary
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. We can see that this slightly elevated fitness of the unaffected female siblings, coupled with the less pronounced decreased fitness of female patients, is sufficient to compensate for the gene loss in the MGM; when we calculate –Δ, the cross-generational reduction of the frequency of females carrying putative pathogenic mtDNA in the general population, using data from the largest-sampled cohort study to date [8], we have ÀΔ < 5:06 Â 10À3 [11] This figure implies that the gene loss can be balanced by de novo mutation in the mtDNA which occurs at a rate of 8:8 Â 10À4∼1:3 Â 10À2 per locus per generation (4.3 × 10-3 on average) [12].
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