| Schizophrenia is a complex and devastating brain disorder and affects almost 1% of the world's population with similar prevalence throughout diverse cultures and geographic areas. Data from twins, adoptees, and families across studies provided replicable evidence for genetic factors in the etiology of this disease. Decades of extensive efforts have been dedicated to the searching of DNA sequence variations that increase the risk. However, the non-Mendelian complex mode of transmission made genetic studies in Schizophrenia quite difficult. The main approaches used to identify susceptibility genes are linkage and association (linkage disequilibrium) studies and schizophrenia is found to be a polygenic disease rather than a monogenic disease, which is influenced by multiple genes with minor or medium risks, and environment factors as well. Many theories have been proposed to explain the mechanism of schizophrenia.Apoptosis is thought to play a role in neuronal pathology in schizophrenia. Gelsolin is a substrate for one of the most important apoptotic enzymes--caspase-3 and Harms et al used several models of neuronal cell death to demonstrate that gelsolin (GSN) had anti-apoptotic properties correlated to its dynamic actions on the cytoskeleton. Furthermore, a genome-wide expression analysis in schizophrenia identified that GSN was significantly down-regulated in schizophrenia with P value being 0.0033. All the hints suggest that GSN might be a novel candidate gene of schizophrenia. Thus, we performed an association study between GSN and schizophrenia using a cohort of the Han Chinese-based trio family. We genotyped 3 SNPs around the GSN locus in 493 sets of the Han Chinese trio sample using allele-specific PCR. However, no evidence for significant association with schizophrenia was found in the analysis of either single nucleotide polymorphisms or haplotype relative risk. To link the dopaminergic and glutamatergic signaling, two of which are involved in the major hypothesis of the pathophysiology of schizophrenia, a calcium-dependent serine/threonine protein phosphatase, calcineurin, could play a critical role. NMDAR-mediated activation of calcineurin results the dephosphorylation of the dopamine- and cAMP-regulated phosphoprotein. Calcineurin, also called protein phosphatase 2B (PP2B), is widely distributed in tissues, with the highest levels found in brain. David J. Gerber et al performed the first association study of the PP2B related genes and got positive evidence on PPP3CC with their 410 affected families of schizophrenia collected from the United States (US) and South Africa (SA). Also, the location of PPP3CC (8p21.3) coincides with one of the putative schizophrenia susceptibility loci (8p) which was either strongly supported by meta-analysis. We were pushed to take another association analysis on PPP3CC in our large scale Chinese population with denser markers scanning. 1399 patients and 1255 controls from Anhui, Guangxi, and Heilongjiang provinces of China were recruited in the case-control analysis which studied 9 SNPs. Unfortunately, negative result obtained was contrary to Gerber's family based investigation. For the purpose of solid confirmation, we decided to replicate several markers either from Gerber's work and our previous work in different subgroup (Shanghai and Jilin) of Chinese population. Another case-control test (619 cases, 601 controls) and trios analysis (352 probands and their biological parents) were taken. Still, no significant association was found with the single marker analysis and haplotype analysis showed the same trend. With the large sample size of Chinese population in different subgroups used and the totally 11 SNPs genotyped, we were quite confident to basically exclude this gene from the candidates of schizophrenia.
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