¶ … Candidate Genes for Schizophrenia Their Impact on Neuro-development

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Brief Introduction -- Schizophrenia is a mental disorder, which is characterized by delusions, lack of drive and interest, changed or unusual emotional reactions and generally disorganized behavior (Kirov et al. 2012). Some signs may begin from childhood but main features become apparent in the late teens and early adulthood. Outcomes and treatment are varied but relapses are frequent. Remissions are also often only partial along with significantly reduced social and occupation involvement. Persons with this disorder are among the most vulnerable, ostracized, and thus disadvantaged in society. A recent meta-analysis reported that about 15.2 out of every 100,000 persons are afflicted with it (Kirov et al.).

Genetic epidemiological studies theorize that varied susceptibility to schizophrenia appears to be strongly genetic (Kirov et al. 2012). These studies have identified many potentials links between genes and chromosomal abnormalities. Increasing evidence sustains the link between the disorder and candidate genes. These discoveries and assumptions enhance current understanding of the disease, its cause or causes and the consequent development of more effective ways of treating it (Kirov et al.).

I The Best Three Candidate Genes for Schizophrenia and Their Impacts

These are loci 119 SDCCAG8, 117 VRK2, and 106 SOX2-OT.

SDCCAG8 Gene

Although its function is still widely unknown, SDCCAG8 has been linked with nervous disorders like Schizophrenia, nephronophthisis and the Bardet-Biedl Syndrome (Insolera et al. 2014). Studies reveal how this gene regulates the accumulation of periocentriolar material and its neuronal polarization and migration in the cortex of mouse subjects. Results of the studies point to the selective increase of this gene in newborn mice before they could walk. Results also showed that the suppressed expression by short-hairpin RNA or non-functioning allele inhibits the recruitment of y-tubulin and pericentrin disturbs microtubule organization. The suppressed expression also separates the centrosome and the nucleus and disturbs neuronal migration (Insolera et al.).

SDCCAG8 also interacts and moves along with periceniolar material 1 (Insolera et al. 2014). Pericenriolar material 1 is a protein, which is essential to targeting protein in the centrosome. One critical finding was that an expression of SDCCAG8, which carries a human mutation can be indicative of neuronal migration defects. Findings of these studies strongly suggest the significant role of the gene in regulating the centrosomal properties and function. At the same time, findings provide the basis for the connection between neurological defects and SDCCAG8 mutations (Insolera et al.).

The Schizophrenia Psychiatric Genome-wide Association Study Consortium isolated 81 single-nucleotide polymorphisms or SNPs, which it found to moderately suggest schizophrenia (Hamshere et al. 2012). Independent follow-ups pointed to seven as specifically significant genomoe-wide. However, multi-locus tests revealed that some of the SNPs, which were not assigned genome-wide significance, appeared to possess genuine link to the mental disorder. A high 47% of the SNPs, along with prior GWS SNPs, were found to be with the PGC-associated allele (Hamshere et al. 2012), according to a recent study. A group of 2,640 respondents with clinically diagnosed schizophrenia were found to possess 78 of the 81 SNPs. The new information was merged with those of the PGC. The combination yielded variants of three loci, one of which was SDCCAG8. The finding provided a high level of support for the association between the three genes and alleles of schizophrenia and bipolar disorder at 21% (Hamshere et al.).

The results of the study confirm the association between the schizophrenia and the PGC and between the three loci genes already identified by GWS in schizophrenia (Hamshere et al. 2012). The results also serve as the first GWS evidence for SDCCAG8 and the two other lici in schizophrenia. The large number of independent replications and the value of the samples used in this particular study combine to produce a 98% confidence interval from the base original of 78 SNPs as true links (Hamshere et al.).

VRK2 Gene

Recent studies on the probable risks of schizophrenia came up with a new variant called VRK2 or rs2312147 at vaccinia-related kinase2 gene (Sohn et al. 2014) drawn from multiple Asian and European samples. But the little-known effect of this gene on the brain structure in schizophenia led to the conduct of a succeeding study on the dearth. This study analyzed the brain structure of 36 schizophrenia patients and 18 VRK2-free volunteers. It used brain magnetic resonance scans and analyses of the gray and white matter on both groups. The Positive and Negative Syndrome Scale...

The tests found no significant difference between the gray matter or white matter connection with the gene in the gene-free volunteers. But significant differences were found in the white matter connection between the gene and schizophrenia patients of the CT/TT genotype groups. The gene affected the splenium of corpus callous,, the left occipital lobe of the white matter, the internal capsul at the left anterior limb and the right retrolentricular portion, the bilateral temporal lobe also of the white matter, the left fornix, the left cingulated gyrus of the white matter and its left parietal lobe.
in the group with the gene. The Digit Symbol Test scores likewise established a correlation in the white matter tracks in CT/TT genotypes and the genotype group with the VRK@ gene. Findings of this study will enhance evidence on the effect of the gene on the white matter of persons with schizophrenia (Sohn et al.).

In response to the need to replicate additional samples in identifying schizophrenia susceptibility genes, another study was conducted on five genome-wide supported variants in the hope of getting close to the real answers (Li et al. 2012). This study gathered a Han Chinese sample bearing the variant rs2312147 at VRK2. The meta-analysis used combined Asian and European volunteers, totaling 7,498. It found the variant in the brain structure of health volunteers' total brain and white matter volume. Analyses suggested the presence of the gene in he schizophrenia patient volunteers. The findings, thus, offer further evidence of the contribution of the gene to schizophrenia (Li et al.).

The gene VRK2 is found on the human chromosome 2p16.1 (Li et al. 2012). Stefansson and his team (2009) first took note of the gene when they chanced upon and reported on several risks of schizophrenia in their sample of 47,536 European subjects. The team found the variant located at about 50 kb of the gene and marked it as a risk for schizophrenia in their study, although its significance had not yet been recognized genome-wide. Nonetheless, in 2011, Steinberg and his team confirmed the link between the variant and the mental disorder in their combined sample. Their studies were, however, conducted only on European volunteers at a time when the association between the disorder and the variant among distant ethnic groups was not the usual mode. But this present study underscores the significant link between the variant and the disorder among Asians. It confirms and bolsters previous findings on the role of VRK2 in the susceptibility to schizophrenia. It enhances the belief that VRK2 is a risk gene for the disorder (Li et al.).

II Their Impact on Neuro-Development

SOX2-OT Gene

Ng and his team (2012) noted that long-coding RNAs abound in mammalian chromosomes, particularly in the brain. The team isolated a group of long non-coding RNAs or lncRNAs, including RMST, which are necessary for proper neurogenesis. RMST lies in the brain and regulated by REST, a transcriptional repressor. RMST increases during the process of neuronal differentiation. This is its very significant role in neurogenesis. It interacts with the SOX2 gene, which in turn regulates the fate of the process. RMST and SOX2 together regulate many genes involved in neurogenesis. Genome-wide binding studies reveal that RMST is needed to lead SOX2 to promote neurogenic processes. The role of RMST as a transcriptional regulator along with SOX2 illustrate their impact on neurogenesis (Ng et al.).

Vondervoort and his team (2013) subscribed to the findings of the earlier studies on the importance of lncRNA in genetic regulation, development, and disease. The interest in lncRNAs has been increasing but the mechanism involved in the control of cellular processes by these RNAs has, however, remained insufficient and uncertain. And greater knowledge and understanding of these mechanisms are important as the genome of most mammals is transcribed. This results in non-coding RNA products. As already discussed in the previous studies, lncRNA is seen to be critically involved in the neurobehavioral and neuro-developmental disorders. It thus possesses functional significance, as its impaired expression has been associated with many intellectual disorders and disabilities. Yet the role of these RNAs is not too known. It is a serious matter to consider, as the consequences of poorly regulated RNAs may result in neuro-developmental disorders (Vondervoort et al.).

The regulation of epigenetic processes particularly during the period of brain development as well as at times of activity-dependent brain tasks influences the formation of many neuro-developmental disorders (Vondervoort et al. 2012). Current evidence shows that lnc RNAs assert significant regulatory effects on the brain at adult and developmental stages. As such, they are a main epigenetic mediator of development processes. The interaction between…