Association Studies On Susceptibility Genes Of Schizophrenia In The Chinese Han Population

Schizophrenia is a chronic, severe mental disorder that affects approximately 1% of the world's population. The disorder is characterized by psychotic symptoms and by cognitive, affective, and psychosocial impairment. Studies of family, twin, and adoption reveal that genetic factors play an important role in the etiological complex of schizophrenia. The inheritance pattern of schizophrenia suggests that there are multiple susceptibility genes, each with individually small effects, which interact with one another and with environmental factors to influence susceptibility to the diseases. In this thesis, we investigated associations between the susceptibility genes and schizophrenia (KIF2 and PDLIM5) in the Chinese Han population using geomic techniques.KIF2 belongs to the kinesin-like protein family and regulates microtubule dynamics at the growth cone edge by depolymerizing microtubules. It plays an important role in the suppression of collateral branch extension. On the other hand, KIF2 is a motor for anterograde transport, and plays an important role in expansion at the nerve growth cone. Homma et al. in 2003 reported that Kif2a knockout mice showed many brain abnormalities, especially in the CA1 and CA3 fields of hippocampal pyramidal cells which are associated with many mental disorders. The extension of collateral growth cones is suppressed in Kif2a+/+ and Kif2a-/- cultured neuron extends more long collaterals without the suppression of Kif2a. Therefore, KIF2 might be one of the susceptible genes of schizophrenia with functional susceptibility. KIF2, the orthologue of Kif2a, maps on 5q12.1 in human genome. On the basis of that KIF2 may be a potential candidate gene for schizophrenia, we selected four common SNPs in the region of KIF2 according to the data in NCBI database and designed appropriate primers for these SNPs. Then we acquired the genotypes of four common SNPs in the sample of 280 nuclear family of the Chinese Han population using the allele specific PCR technology, and studied the association relationship between the KIF2 gene and schizophrenia using ETDT, 2LD, Hapview and FBAT softwares. None of the four markers we selected in the KIF2 gene revealed transmission distortion in the trios. However, a common two-SNP haplotype (rs2289883/rs464058, G/A) showed a significant association with schizophrenia. In addition, a four-SNP haplotype (T/G/A/G) with a frequency of 23.4%, which was identified in parental chromosomes, showed a significant association with schizophrenia (P = 0.00795). Our results demonstrate that the KIF2 gene, located at 5q12.1, is a potential schizophrenia susceptibility gene. The PDZ and LIM domain 5 protein (PDLIM5) contains one PDZ (postsynaptic density-95/discs large/zone occludens-1) domain and three LIM (Lin-11, Isl-1, and Mec-3) domains, which is also thought as enigma-homologue LIM domain (ENH) protein or LIM protein. As a member of the Enigma class of proteins, LIM domain containing protein is involved in cytoskeleton organization, cell lineage specification, organ development, and oncogenesis. The enigma-homologue LIM domain (ENH) protein was expressed in various regions of the brain, most notably in the hippocampi, cortex, thalamus, hypothalamus, amygdala, and cerebellum. In hippocampal neurons, ENH appears to be localized in presynaptic nerve terminals. PDLIM5 is also a homolog of the AD-associated neuronal thread protein (AD7c-NTP), which is over-expressed in Alzheimer disease sufferers, beginning early in the course of the disease. Iwamoto et al. compared the mRNA levels of PDLIM5 in the lymphoblastoid cell lines (LCLs) and postmortem brains of subjects with mental disorders with those of controls. They found that the mRNA level of PDLIM5 was decreased in the lymphoblastoid cells derived from patients with schizophrenia and bipolar disorders, but commonly increased in the postmortem brains of patients with schizophrenia, bipolar disorders, and major depression. Moreover, Kato et al. provided confirmation of up-regulation of the mRNA level of PDLIM5 in an independent brain sample set obtained from the Stanley Array Collection. On the other hand, PDLIM5 is located on human chromosome 4q22.3, which was suggested a hotspot region with susceptibility genes of schizophrenia by several independent linkage studies. These evidences imply that PDLIM5 is a potential susceptible gene for schizophrenia. In this work, we selected six common SNPs in the region of PDLIM5 according to the previous studies and the information of PDLIM5 in NCBI and HapMap databases and designed appropriate primers for these SNPs. Then we acquired the genotypes of the six common SNPs in the case-control samples of Jiangxi province using the single nucleotide primer extension method, and studied the association relationship between the PDLIM5 gene and schizophrenia using Hapview and COCAPHSE softwares. Among six SNPs we selected, rs2433322 showed significantly different frequencies between cases and controls (P=0.000010). Haplotypes constructed by rs2433322 were also significantly associated with schizophrenia (Global P=0.00019 even after strict Bonferroni correction). Our results provide further evidence to support PDLIM5 as a potential susceptible gene for schizophrenia.