Paradox of schizophrenia genetics: is a paradigm shift occurring?

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.

Attempts to replicate genetic associations with schizophrenia in a cohort from north India

“…We focused primarily on the chromosome 6p region, which harbors the strongest and most consistently replicated susceptibility loci in the GWASs. 6 , 16 , 17 , 43 Our analyses modestly support some of the prior associations, 42 , 43 while indicating that there are possibly other associations specific to this population, which remains to be identified.…”

“… 47 More recently, SNPs from this gene have been included in a SZ database (www.szgenes.org). 42 , 43 However, this gene has not been found to be associated with SZ in any GWASs or PGC GWAS. In an ab initio analysis, AHI1 was identified as a common helper provirus integration site for murine leukemias and lymphomas.…”

On the origin of schizophrenia: Testing evolutionary theories in the post‐genomic era

“…Recently, the view on genetic basis of schizophrenia has been made even more complicated by introducing the mitochondrial genome into consideration. Sex differences in schizophrenia onset and severity have led some authors to conclude that mitochondrial DNA might explain the evolutionary paradox of the disorder . Some studies indicate that schizophrenia is more commonly inherited through maternal compared to paternal lineage (although this has not been consistently replicated), which is in accordance with the mode of transmission of mitochondrial DNA .…”

“…The same allele may not show the association with schizophrenia in a study with severely affected subjects. In fact, an allele detected in a group with more severe schizophrenia implies that it could be a facilitating nuclear allele, reinforcing the deleterious effect of a mitochondrial mutation . If the mitochondrial genome model is true, it imposes novel views on genetic variability underlying the functioning of the brain and all psychiatric disorders.…”

Genetic aspects of schizophrenia

“…В цереброспинальной жидкости при шизофрении обнаружены [39] сниженные уровни как D-серина, так и общей фракции этой аминокислоты. К тому же некоторые симптомы шизофрении успешно нивелируются при добавлении серина к лечению [40]. Снижение уровня D-серина вносит значительный вклад к гипофункции NMDA-рецепторов при шизофрении.…”