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Schizophrenia genetic risk factors
More recent genetic researches on schizophrenia have been based on SNP-related genome wide association studies. Significant associations with markers spanning major histocompatibility complex region on 6p21.3-22.1, a marker upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2 implicate immune, developmental and cognitive components to schizophrenia risk. Schizophrenia association to MHC, NRGN and TCF4 were conducted using genome-wide scan of 2,663 schizophrenia cases and 13,498 controls from eight European locations. Twenty-five markers with P value less than 1 × 10−5 were followed up from additional samples. As a result, association studies found markers on MHC, 11q24.2 and 18q21.2 with genome-wide significance. Additional researches have shown linkage with five new loci 1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33 where the common target mir-137 was found significant (Schizophrenia Psychiatric Genome-Wide Association Study Consortium, 2011). Joint analysis with bipolar samples also showed CACNA1C, ANK3 and ITIH3-ITIH4 region with genome-wide significance. However, polymorphism and risks for schizophrenia in these regions remain insignificant without considering their molecular functions in causing psychotic symptoms.

miRNA in schizophrenia
MicroRNA, as a non-coding RNA, has been suggested to play a significant role in regulating dendrite development and phenotypical maturation of new neurons in adult mammalian brain. Researches have found that DNA methylation mediator methyl-CpG-binding protein 2 (MECP2) regulated proliferation and differentiation of adult hippocampal neural progenitors through modulating mir-137 expression. In addition, mir-184, as a direct target for MBD1, also promotes proliferation of adult hippocampal neural progenitors (Liu et al., 2010). Interestingly, using RT-PCR to assess microRNA expression in high- grade astrocytomas and adult mouse neural stem cells, researchers found that mir-137 inhibited proliferation of glioblastoma multiforme cells and induced differentiation of brain tumor stem cells, offering another insight for mir-137 significance in regulating neurogenesis. While associations using GWAS have been established between mir-137 region and schizophrenia, such regulatory function in neurogenesis explains why disturbance in mir-137 expression results in higher risk for schizophrenia susceptibility.

Association to voltage-gated calcium channel proteins
As for linkages to CACNA1C region, CACNA1C modulates calcium channel to regulate neurological activities. Activation of CACNA1C gene in hippocampus and neocortex was shown to affect NMDA independent LTP in hippocampus, suggesting an alteration in memory and also explaining psychological symptoms common in bipolar, schizophrenia and autism. . Similar to CACNA1C in the ability to regulate LTP, neurogranin (NRGN) is a main postsynaptic protein regulating calmodulin-Ca2+ level by binding calmodulin in the absence of Ca2+. Further experiments have shown that NRGN mediates enhancement of synaptic strength due to its ability to target calmodulin within dendritic spines. Despite the fact that genome wide association studies allow us to identify high risk loci for schizophrenia, these genetic researches are unable to explain how these proteins function in the molecular level and how do they interact if at all with each other and how are they regulated for schizophrenics compared to the normal population. However, hypotheses can be made based on the functions that are already known for these genetic loci.

A recent multi-stage schizophrenia genome-wide association study of 36,989 cases and 113,075 controls has identified 128 independent associations spanning 108 conservatively defined loci. These loci offered several insights in understanding schizophrenia. The associated loci included DRD2 - the target for anti-psychotic drugs and other genes involved in glutamatergic neurotransmission. Associations with CACNA1C, CACNB2 and CACNA1I were also found and expand on what was already known for voltage-gated calcium channels in schizophrenia. In this extensive research, a comparison with the 1000 Genomes Project reference panel was also used and independent single nucleotide polymorphisms was tested using meta-analysis. Meta-analysis, as the quantitative, formal, epidemiological study design used to derive conclusions for current research, provide current genetic studies with more precise estimations of schizophrenia associated genes. Enrichments were found, in addition to enhancer expression in neurons and glia, in enhancers for CD19 and CD20 lines after mapping active enhancers in 56 different tissues and cell lines, providing possible linkage of acquired immunity to schizophrenia. However, researches has already found associations of the innate immunity, more specifically, the classic and lectin pathway’s importance in schizophrenia.

Linkage to C4 complement protein
Structural variations of complement C4 has been studied genetically for their relative risk level for schizophrenia. The C4 allele was found to generate varying levels of C4A and C4B in the brain and a greater expression of C4A proportions to a higher risk for schizophrenia. Four common C4 structural haplotypes were studied after analyzing the inheritance in father-mother-offspring trios. Several facts have been established after studying RNA expression of C4A and C4B in 674 brain samples. C4A and C4B RNA expression increased proportionally with their copy numbers; the expression levels for C4A were three times greater than that of C4B; C4-HERV enhancer increased ratio of C4A to C4B expression. The observation that risks for schizophrenia in specific structural variants were consistent regardless of MHC haplotypes substantiated that schizophrenia risks indeed from C4 structural variations. C4A, especially C4A long homolog was also found to be more strongly associated with schizophrenia risks than C4B. The different significance for C4A and C4B in schizophrenia patients may be explained by their structural differences. The thioester bond of nascent C4b of the C4A isotype preferentially transacylates onto the amino group, whereas acylation of hydroxyl groups is strongly preferred in C4b isotype, resulting in different structures and affinities in the complement system. In addition, it was found that C3b:C3a hemolytic activity ratio was about 4:1 (Isenman et al., 1984), offering a possible explanation of the observation that the expression levels for C4a were three times greater than that of C4b

Association of C4 gene to schizophrenia was also supported by researches focusing on the molecular levels of complement proteins concentrations in schizophrenia patients. However, the data were controversial between different studies. In 2005, a research done by Hakobyan showed that the total hemolytic activity of complement and activities of individual components, C1, C3 and C4 were significantly higher in schizophrenic patients. C4 concentration was found to decrease significantly in schizophrenic patients compared with healthy controls for a research in 2008 for ninety-six subjects from Armenian population. However, an earlier research conducted on 27 schizophrenics, 23 manic, 29 depressed and 21 normal subjects indicated significant higher plasma C4 for schizophrenics than the normal population. The discrepancies are likely resulted by the fact that in the earlier research, patients were previously treated with haloperidol, perphenazine or thioridazine. Another factor that was not addressed is the genetic differences for C4 genes in different populations. Although the earlier researches had multiple variables and were likely biased due to the small population tested, the discrepancy informs in some extent that although C4 gene showed linkages to schizophrenia, its level is unlikely causal to the disease, revealing a limitation in genetic approaches for diseases in establishing causal relationships.