Candidate Genes for Schizophrenia and Neurodevelopmental Impact

Introduction to Schizophrenia and Genetic Susceptibility

Schizophrenia is a mental disorder characterized by delusions, lack of drive and interest, unusual or altered emotional reactions, and generally disorganized behavior (Kirov et al. 2012). Some signs may begin in childhood, but the main features typically become apparent in late adolescence and early adulthood. Outcomes and treatment vary considerably, and relapses are frequent. Remissions are often only partial, and the disorder is associated with significantly reduced social and occupational functioning. Persons with this disorder are among the most vulnerable, stigmatized, and disadvantaged in society. A recent meta-analysis reported that approximately 15.2 out of every 100,000 persons are affected by it (Kirov et al.).

Genetic epidemiological studies theorize that varied susceptibility to schizophrenia is strongly genetic in origin (Kirov et al. 2012). These studies have identified many potential links between genes and chromosomal abnormalities. Increasing evidence supports the association between the disorder and specific candidate genes. These discoveries enhance current understanding of the disease, its etiology, and the consequent development of more effective treatments (Kirov et al.).

SDCCAG8: Centrosomal Function and Neuronal Migration

The three strongest candidate genes for schizophrenia are loci 119 SDCCAG8, 117 VRK2, and 106 SOX2-OT. Although the function of SDCCAG8 is still not fully understood, it has been linked to neurological disorders such as schizophrenia, nephronophthisis, and Bardet-Biedl Syndrome (Insolera et al. 2014). Studies reveal how this gene regulates the accumulation of pericentriolar material and governs neuronal polarization and migration in the cortex of mouse subjects. Results point to a selective increase in expression of this gene in newborn mice prior to ambulation. Results also showed that suppressed expression — achieved through short-hairpin RNA or a non-functioning allele — inhibits the recruitment of γ-tubulin and pericentrin, thereby disrupting microtubule organization. Suppressed expression further separates the centrosome from the nucleus and disturbs neuronal migration (Insolera et al.).

SDCCAG8 also interacts with and moves alongside pericentriolar material 1 (Insolera et al. 2014). Pericentriolar material 1 is a protein essential to targeting other proteins to the centrosome. One critical finding was that an expression of SDCCAG8 carrying a human mutation can be indicative of neuronal migration defects. These findings strongly suggest the significant role of the gene in regulating centrosomal properties and function, while also providing a basis for understanding the connection between neurological defects and SDCCAG8 mutations (Insolera et al.).

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

The results confirm the association between schizophrenia and the PGC, and between the three loci already identified by genome-wide studies in schizophrenia (Hamshere et al. 2012). They also represent the first genome-wide significant evidence for SDCCAG8 and the two other loci in schizophrenia. The large number of independent replications and the quality of the samples produced a 98% confidence interval from the original 78 SNPs as genuine links (Hamshere et al.).

VRK2: White Matter Connectivity and Schizophrenia Risk

Recent studies on the probable risk factors of schizophrenia identified a new variant, VRK2 (rs2312147), at the vaccinia-related kinase 2 gene (Sohn et al. 2014), drawn from multiple Asian and European samples. The limited understanding of this gene's effect on brain structure in schizophrenia prompted a subsequent study to address this gap. That study analyzed the brain structures of 36 schizophrenia patients and 18 VRK2-free volunteers using brain magnetic resonance imaging and analyses of gray and white matter in both groups. The Positive and Negative Syndrome Scale and Digit Symbol Test were administered to schizophrenia patients. No significant differences in gray matter or white matter were found in the gene-free volunteers. However, significant differences in white matter connectivity were identified in schizophrenia patients of the CT/TT genotype groups. The gene affected the splenium of the corpus callosum, the left occipital lobe of the white matter, the internal capsule at the left anterior limb and the right retrolenticular portion, the bilateral temporal lobe white matter, the left fornix, and the left cingulate gyrus and left parietal lobe of the white matter in the group carrying the gene. Digit Symbol Test scores also established a correlation with white matter tracts in CT/TT genotypes. These findings enhance the evidence for the effect of VRK2 on white matter in persons with schizophrenia (Sohn et al.).

In response to the need to replicate findings across additional samples for identifying schizophrenia susceptibility genes, another study examined five genome-wide supported variants (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 participants. It identified the variant in the brain structure of healthy volunteers in terms of total brain and white matter volume. Analyses suggested the presence of the gene in schizophrenia patient volunteers, offering further evidence of the gene's contribution to the disorder (Li et al.).

The gene VRK2 is located on human chromosome 2p16.1 (Li et al. 2012). Stefansson and colleagues (2009) first identified the gene when they reported on several schizophrenia risk factors in a sample of 47,536 European subjects. The team found the variant located approximately 50 kb from the gene and flagged it as a schizophrenia risk factor, though its genome-wide significance had not yet been established. In 2011, Steinberg and colleagues confirmed the link between the variant and the disorder in a combined sample, although their studies were conducted exclusively on European volunteers. The present study underscores the significant association between the variant and the disorder among Asian populations, confirming and strengthening previous findings on the role of VRK2 in schizophrenia susceptibility and reinforcing the view that VRK2 is a risk gene for the disorder (Li et al.).

Conclusion

Genetic epidemiological research has progressively identified candidate genes such as SDCCAG8, VRK2, and SOX2-OT as meaningful contributors to schizophrenia susceptibility. Each gene illuminates a distinct aspect of the disorder's neurobiological basis — from centrosomal regulation and neuronal migration, to white matter connectivity, to the epigenetic control of neurogenesis through long non-coding RNA. Continued advances in molecular genetic methodology, particularly those enabled by the Human Genome Project, offer the best prospects for improved diagnosis, prognosis, and treatment of schizophrenia and related neurodevelopmental disorders.