Niufan Gu

Family-based association study of DTNBP1 in 6p22.3 and schizophrenia

P1328 (rs742105) T C T C C P1655 (rs2619539) G G C C C P1763 (rs2619522) T T T T G P1578 (rs1018381) C C C C T P1583 (rs909706) A A G G G Estimated probability 0.37 0.26 0.12 0.1 0.05 O 183.83 115.31 60.16 41.67 22.08 E 166.69 116.46 55.57 46.72 22.89 Var(O E) 47.17 42.84 23.45 18.37 11.04 w (1 df) 6.22 0.03 0.90 1.39 0.06 P-value 0.01 0.86 0.34 0.24 0.81 Global P-value 0.00072 Molecular Psychiatry (2003) 8, 1008 & 2003 Nature Publishing Group All rights reserved 1359-4184/03

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

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Further evidence for the association between G72/G30 genes and schizophrenia in two ethnically distinct populations

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 …

A family-based study of the association between the G72/G30 genes and schizophrenia in the Chinese population

Recently, the nested genes G72 and G30 on chromosome 13q32–q33 have been implicated in the etiology of schizophrenia. We genotyped six single-nucleotide polymorphisms (SNPs: rs3916965, rs3916967, rs2391191, rs778294, rs779293 and rs3918342), which span approximately 82.5 kb in the region encompassing the G72/G30 genes in 1176 Han Chinese subjects (588 cases and 588 controls) and 365 Scottish subjects (183 cases and 182 controls). Significant association between an allele of marker rs778293 and schizophrenia was found in our Chinese samples (P=0.0013), and was replicated in the Scottish samples (P=0.022). LD analysis revealed that four SNPs between rs3916965 and rs778294 were in LD, called block I, and the two distal SNPs (rs778293 and rs3918342) constituted a block II in both the Chinese and Scottish samples. We selected one SNP from each block (rs778294 from block I and rs778293 from block II), and then analyzed the haplotypes. A significant difference was observed for the common haplotype GC in the Chinese sample (P=0.0145), and was replicated in the Scottish sample (P=0.003). On meta-analysis, we separately analyzed the studies in Asian and European populations because of significant heterogeneity in the homogeneity test. We found a statistically significant association between rs778293 and schizophrenia in Asian populations, but no difference was found between cases and controls in the European populations. Overall, our data give further support to the existing evidence that G72/G30 genes are involved in conferring susceptibility to schizophrenia.

Association of DAAO with schizophrenia in the Chinese population.

Studies have shown a strong positive association between schizophrenia and G72/G30, demonstrated by both individual markers and haplotypes. A further functional study also supports the role of G72 in the etiology of schizophrenia. In this study, we have replicated these results of transmission/disequilibrium testing (TDT) and haplotype analysis in the Han Chinese population, showing P values of 0.0018 and 0.00007 for individual markers and haplotypes, respectively. Hence, our data supports the hypothesis that G72/G30 are important candidate genes for explaining schizophrenia in the Han Chinese population.

Response to chlorpromazine treatment may be associated with polymorphisms of the DRD2 gene in Chinese schizophrenic patients

Recently, the gene called DAAO was reported to be associated with schizophrenia in the French Canadian populations. Here, we report a result obtained in the study of our large collection of 547 schizophrenia cases and 536 controls in the Chinese population. Six single-nucleotide polymorphisms (SNPs) were genotyped at and around the DAAO locus, covering a 10-kb region entirely encompassing the complementary DNA sequences of DAAO. We found statistically significant differences in allele distributions on one marker: SNP rs3741775 (P = 0.0000001). In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese.

An association between polymorphisms of the interleukin-10 gene promoter and schizophrenia in the Chinese population

Previous studies have demonstrated that the -141C Ins/Del and TaqI A polymorphisms in the DRD2 gene affect the density of the dopamine D2 receptor. The present study examines the correlation between these two polymorphisms and the therapeutic response to chlorpromazine, a typical antipsychotic drug, in 135 inpatients with schizophrenia. Clinical symptoms were evaluated using the Brief Psychiatry Rating Scale (BPRS) before and after 8 weeks of treatment with 300-600 mg/day of chlorpromazine. Our results show that genotyping -141C Ins/Del may help to predict the efficacy of chlorpromazine treatment (P=0.01) due to the fact that patients with no Del allele showed greater improvement than those with Del allele on the overall BPRS (P=0.03), and that, therefore, the potential for therapy in patients with schizophrenia is related to the -141C Ins/Del polymorphism in the DRD2 gene. However, no such relationship was found for the TaqI A polymorphism.

Association analysis between mood disorder and monoamine oxidase gene

Immunological abnormalities have been found to be associated with schizophrenia for decades. Cytokines are key proteins involved in the immune system activation. Interleukin-10 (IL-10), an important immunoregulatory cytokine, is located on chromosome 1q31-32, a region previously reported to be linked to schizophrenia in genetic studies. Thus, a study was carried out on the association between schizophrenia and three single nucleotide polymorphisms in the promoter region of IL-10 gene. Totally, 341 patients and 334 controls of Chinese descent were analyzed. Statistically significant differences were observed in both allelic and genotypic frequencies of the -592A/C polymorphism (Allele, chi(2)=4.43, df=1, P=0.032, odds ratio (OR)=1.26, 95% CI 1.02-1.56; Genotype, chi(2)=6.18, df=2, P=0.044) while the other two polymorphisms did not show such differences. The observed haplotype distributions revealed a significant association with schizophrenia (P=0.0008). These data suggest that the IL-10 gene may confer susceptibility to the development of schizophrenia in the Chinese population.

Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia

To ascertain whether mood disorders, including bipolar and unipolar, are genetically associated with the monoamine oxidase A (MAOA) or monoamine oxidase B (MAOB) gene in the Chinese population, 132 cases of mood disorder and 88 normal controls were genotyped for the MAOA(CA)n, MAOB(GT)n, and MAOB(TG)n loci by the method of amplification fragment length polymorphism. Among 132 cases with mood disorder, eight alleles (size: 112-126 bp) of locus MAOA(CA)n, 12 alleles (size: 168-198 bp) of locus MAOB(GT)n, and nine alleles (size: 195-213 bp) of locus MAOB(TG)n were observed. Comparison of the allele frequency of the three loci showed no difference between mood disorder cases and normal controls on average. When each group was stratified into several subgroups, significant differences were found. On the MAOA(CA)n locus, the frequency of 116 bp allele was higher in the female bipolar disorder cases (0.2581) compared with that in the female unipolar disorder patients (0.1154) (Z=2.15, p<0. 05). On the MAOB(GT)n locus, the frequency of 180 bp allele was higher in bipolar disorder patients (0.1579) than that in normal controls (0.0678) (Z=2.05, p<0.05). The frequency of this allele was even higher in female bipolar disorder patients (0.1719) than that in female normal controls (0.0541). On the MAOB(TG)n locus, the frequency of 205 bp allele was higher in female bipolar disorder patients (0.6406) than that in female normal controls (0.4375) (Z=2. 17, p<0.05). For the unipolar disorder patients, the frequency of this allele was higher in female cases (0.5222) than that in male cases (0.1818) (Z=3.49, p<0.05). As for association studies, significant association between bipolar disorder and MAOB gene was detected. For the 180 bp allele of MAOB(GT)n, the relative risk (RR) of biploar versus normal control was 2.58 (p<0.05), and the RR of female bipolar disorder versus female normal control was 3.63 (p<0. 05). For the 205 bp allele of MAOB(TG)n, the RR of female bipolar disorder versus female normal control was 2.29 (p<0.05). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:12-14, 2000.

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

The object of this study is to assess 1) the relationship between plasma antipsychotic drug concentration, serum prolactin levels and the clinical efficacy of risperidone, 2) the relationship between the CYP2D6 polymorphisms and metabolizing of risperidone and 3) the role of 9-hydroxyrisperidone in elevating prolactin levels. One-hundred and eighteen Chinese schizophrenia patients (40 males, 78 females, age 15—60 years) were given risperidone at dosages ranging from 2—8 mg/day for 8 weeks. Clinical efficacy was determined using the Brief Psychiatric Rating Scores (BPRS). Serum prolactin levels were assayed before and after the 8 week treatment and plasma risperidone and 9-hydroxyrisperidone levels were also measured at the end of the 8-week treatment. The results showed there was no significant correlation between the concentration of active moiety and clinical response. Risperidone treatment significantly increased serum prolactin levels. Furthermore, changes of prolactin levels were not correlated with the clinical response. For the risperidone/ 9-hydroxyrisperidone ratio, there was a statistically significant difference among the CYP2D6*1/*1, *1/*10, *10/*10 genotypes (Kruskal—Wallis test, p = 0.012). No significant differences were found in the concentration of 9-hydroxyrisperidone and active moiety among the genotypes. In addition, the concentration of 9-hydroxyrisperidone was not significantly correlated with the increase of serum prolactin. In conclusion, our study has, for the first time, produced evidence that in Chinese schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6. Neither changes in serum prolactin levels nor plasma concentration of active moiety were significantly correlated with clinical efficacy of risperidone. 9-hydroxyrisperidone may not play a predominant role in elevating serum prolactin level.