Shaomin Zhu

A case control and family based association study of the neuregulin1 gene and schizophrenia

Data from twin, family, and adoption studies provide strong evidence that genetic factors play a major aetiological role in schizophrenia. By a series of linkage studies, chromosome 8p has been implicated as a region harbouring a schizophrenia susceptibility gene.1–4 Recently, Stefansson and colleagues reported that neuregulin 1 (NRG1 ), located in 8p21-12, may be involved in the aetiology of schizophrenia.4,5 In their linkage and association studies, a 290 kb core at risk haplotype at the 5′ end of NRG1 was found to be strongly associated with schizophrenia in Icelandic and Scottish populations. This haplotype contains the first exon of NRG1 , which encodes a part of glial growth factor 2 ( GGF2 ). Deficiency of glial growth factors has been presumed to be implicated in the pathogenesis of schizophrenia.6 Futhermore, NRG1 mutant mice have fewer functional N-methyl D-aspartate(NMDA) receptors than wild type mice, and display stereotypic behavioural abnormalities similar to those of normal mice treated with the psychogenic drug phenylcyclidine.4 This core at risk haplotype was defined by five single nucleotide polymorphisms (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, SNP8NRG243177, SNP8NRG433E1006) and two microsatellites (478B14-848, 420M91395). The frequency of this haplotype in schizophrenic individuals was higher than in controls; in Icelandic samples the frequency was 15.4 (7.5%; p  =  0.000087).4 The first replication using Scottish samples revealed a similar result at 10.2 (5.9%; p  =  0.00031).5 Another replication performed by Williams et al with British or Irish samples used one SNP and the two microsatellites of the core at risk haplotype. However, the association was much weaker at 9.5 (7.5%; p  =  0.04).7 Yang et al reported other markers located in the middle of NRG1 and associated with schizophrenia, in a Chinese population.8 Another independent analysis using 13 microsatellites found two groups of haplotypes, which were significantly …

Functional Variants in the Promoter Region of Chitinase 3–Like 1 (CHI3L1) and Susceptibility to Schizophrenia

The chitinase 3-like 1 gene (CHI3L1) is abnormally expressed in the hippocampus of subjects with schizophrenia and may be involved in the cellular response to various environmental events that are reported to increase the risk of schizophrenia. Here, we provide evidence that the functional variants at the CHI3L1 locus influence the genetic risk of schizophrenia. First, using case-control and transmission/disequilibrium-test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2 x 10(-7)) and was associated with lower expression (P=3.1 x 10(-5)) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. Our findings identify CHI3L1 as a potential schizophrenia-susceptibility gene and suggest that the genes involved in the biological response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia.

A Case-control association study between the GRID1 gene and schizophrenia in the Chinese Northern Han population

The glutamatergic dysfunction hypothesis of schizophrenia implicates the genes involved in glutamatergic transmission as strong candidates for schizophrenia-susceptibility. Recent linkage and association studies have identified the glutamate receptor, ionotropic, delta 1 gene GRID1 on 10q22 as a strong candidate for schizophrenia. In this current association study, we genotyped five genetic variants within the GRID1 gene in 567 Chinese Han subjects recruited from Northeast of China (260 schizophrenics and 307 normal controls). Four SNPs, rs1902666 (P=0.024), rs2814351 (P=0.027), rs11591408 (P=0.0000107) and rs999383 (P=0.000093) were found to be significantly associated with schizophrenia. Haplotype analysis also revealed significance with global P values of 0.0081 and 0.00076 for SNPs 1-2 and SNPs 3-4-5 haplotypes, respectively. Our results strongly support previously reported association studies, implicating GRID1 in the etiology of schizophrenia.

Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population.

Results of gene expression microarray and quantitative PCR studies have suggested abnormalities in the expression of myelin-related genes including myelin-associated glycoprotein (MAG) in schizophrenic patients. Research provides strong evidence for oligodendrocyte dysfunction in schizophrenics. In order to further assess the role of MAG in schizophrenia, we examined four single nucleotide polymorphisms (SNPs), namely rs2301600, rs3746248, rs720309 and rs720308, of this gene in Chinese schizophrenic patients (n=470) and healthy controls (n=470). The distribution of rs720309 T/A genotypes showed a strong association with schizophrenia (chi(2)=14.58, d.f.=2, P=0.0008). A haplotype constructed of rs720309-rs720308 also revealed a significant association with schizophrenia (chi(2)=11.914, d.f.=3, P=0.0084). Our findings of a significant associations between schizophrenia and the MAG gene suggest that this gene may be involved in susceptibility to schizophrenia in the Chinese Han population.

Family-based association study of Epsin 4 and Schizophrenia.

Recently, Pimm et al. identified Epsin 4 on chromosome 5q33 as a susceptibility gene for schizophrenia in the British population, based on linkage and association evidence. In Pimms case-control study, both the single polymorphisms and the individual haplotypes at the 5′ end of the gene showed genetic association with schizophrenia. Here, we report the first study evaluating the relevance of Epsin 4 and schizophrenia outside the British population. Markers showing positive results in the original work as well as two additional polymorphisms were genotyped in 308 Han Chinese family trios. Transmission disequilibrium analysis was used to test for association of single-locus markers and multi-locus haplotypes with schizophrenia. Although no individual marker was significant at the P=0.05 level, the haplotypes detected in our samples, different from those previously reported, showed strong evidence of association (most significant global P=0.0021). Our results indicate the presence of a locus near the 5′ end of Epsin 4 conferring susceptibility to the disease and provide further support for Epsin 4 as an important potential contributor to genetic risk in schizophrenia.

No genetic association between polymorphisms in the AMPA receptor subunit GluR4 gene (GRIA4) and schizophrenia in the Chinese population

The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. It has recently been reported that some haplotypes in the AMPA receptor subunit GluR4 Gene (GRIA4), which is located on chromosome 11q22, are positively associated with schizophrenia in the Japanese population. In order to assess the role of GRIA4 in schizophrenia, we examined three reported positive SNPs (single nucleotide polymorphisms): rs609239, rs641574 and rs659840 at the GRIA4 locus in schizophrenic cases (n = 372) and controls (n = 392) of the Chinese population. Although we had observed similar allele and genotype frequencies compared with that in the Japanese population, no evidence was found for association with the disease in the analysis of either single nucleotide polymorphisms (all P-values > 0.300) or haplotype relative risk (all P-values > 0.088). Our results suggest that the three SNPs of GRIA4 are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.

Evidence for association between single nucleotide polymorphisms in T complex protein 1 gene and schizophrenia in the Chinese Han population

Schizophrenia (MIM 181500) is a severe, common, and heterogeneous psychiatric disorder that affects 1% of the world’s population. The disorder is characterised by hallucinations, delusions, disorganised thoughts, and various cognitive and affective impairments. As a leading cause of psychiatric admissions, schizophrenia accounts for a considerable portion of healthcare expenditure and is a major public health concern. Family, twin, and adoption studies have shown that a genetic factor is associated with susceptibility to schizophrenia.1–4 The number and nature of genes that influence susceptibility to schizophrenic illness, as well as their interaction with environmental factors, are unknown. Despite decades of research on anatomical, physiological, and biochemical changes possibly associated with schizophrenia, insight into the aetiology is only fragmentary. Mapping of genes that contribute to the development of schizophrenic disorders by means of linkage and association studies may help identify and characterise causal factors. Although no single causative gene has been identified to date, several chromosomal loci with positive linkage results are under investigation as tentative susceptibility loci for schizophrenia, including chromosomes 6, 8, 10, 13, and 22 to remove obstacles of locus heterogeneity among sampled populations.5 Cao et al first reported possible linkage to 6q21–22 in two independent American samples of patients with schizophrenia: at locus D6S474 using sibling pair analysis in 63 independent sibling pairs (p = 0.00018) and at D6S424, which is about 14 centimorgan (cM) near D6S474 in a second sample of 87 independent sibling pairs (p = 0.00095).6 The same group reported modest support for linkage to D6S424 in a third sample in 1999 that consisted of 54 American and Australian sibling pairs.7 In a study with combined samples (141 independent sibling pairs), they obtained a non-parametric likelihood of odds (LOD) score of 3.82 (p = 0.000014).7 Several other studies also supported a susceptibility locus for schizophrenia on …

Investigation of variants in the promoter region of PIK3C3 in schizophrenia

The PIK3C3 gene has been implicated as a candidate gene for schizophrenia by functional evidence and genetic association studies. A series of previous studies have found susceptibility SNPs in promoter region. To further verify its susceptibility to schizophrenia in the Chinese population and the function of the polymorphisms, we performed a case control study in 556 unrelated schizophrenia patients and 563 normal controls as well as an in vitro functional analysis. In our association analysis of-432C-/T, we discovered obvious differences in allele frequency between patients and controls (P=0.017). A T/C haplotype constructed by -432C-/T and -86insC, which are tightly linked with each other (r(2)=1) can significantly weaken promoters transcriptional activity by 20% (p=0.002 by t-test). Though we cannot exclude the possibility that susceptibility of -432C-/T is caused by its linkage disequilibrium with other causal variants, our results do support PIK3C3 play a significant role in the etiology of schizophrenia.