Ronglin Che

Apoptotic Engulfment Pathway and Schizophrenia

Background Apoptosis has been speculated to be involved in schizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1, ABCA1 and ABCA7 genes and tested their association with the disease. Methodology/Principal Findings Ten, eleven and five SNPs were genotyped in the GULP1, ABCA1 and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between the ABCA1 and ABCA7 genes in the ISHDSF sample (p = 0.0022) and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 and ABCA1 genes in the ICCSS sample (p = 0.0120). Rs3858075 in the ABCA1 gene was involved in both 2- and 3-marker interactions in the two samples. Conclusions/Significance From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved in schizophrenia in subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease.

Association analysis of serotonin receptor 7 gene (HTR7) and risperidone response in Chinese schizophrenia patients

Several lines of evidence suggest that the human 5-HT(7) receptor may be involved in the pharmacodynamics of risperidone and may influence clinical response of the drug. A pharmocogenetics study of this receptor may therefore be useful in developing individualized therapy. But few studies about it have been done. In this study, we genotyped ten single nucleotide polymorphisms (SNPs) distributed throughout the HTR7 gene and analyzed six of them for association with the reduction of Brief Psychiatric Rating Scale (BPRS) scores in drug-naive Chinese schizophrenia patients, following an eight-week period of risperidone monotherapy. The confounding effects of nongenetic factors were estimated and the baseline symptom score as well as the duration of illness were included as covariates for adjustment. No significant correlation of HTR7 with antipsychotic efficacy was detected in either genotype or haplotype analysis. These results demonstrate that variations in the HTR7 gene may not be good genetic markers for predicting the therapeutic efficacy of risperidone.

Positive association between GRIN2B gene and bipolar disorder in the Chinese Han Population

In the present work we genotyped three single-nucleotide polymorphisms (SNPs) (rs7301328, rs1805247, and rs1805502) of the GRIN2B gene in a set of 480 unrelated bipolar disorder patients and 480 unrelated genetically matched normal controls in Chinese Han population by either allelic-specific multiplex ligation-detection reaction (AMLR) technology or direct sequencing. Rs1805247 and the haplotype consisting of rs1805502 and rs1805247 were significantly associated, suggesting GRIN2B as having a role in the etiology of bipolar disorder.

A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Association study between RGS4 and bipolar disorder in the Chinese Han population.

This abstract concerns a brief association study between RGS4 and bipolar disorder, by an association study of five single nucleotide polymorphisms, rs951436, rs951439, rs2842030, rs2661319, and rs2344671, in 484 patients and 288 controls from the Chinese Han population. In our case–control study, the T allele of the single nucleotide polymorphism rs951436 tended to be protective (P=0.0078), and in addition, a haplotype containing this T allele was also protective for bipolar disorder (P=0.02). Our results provide further evidence to support RGS4 as a potential susceptible gene for bipolar disorder.

No association between the FXYD6 gene and schizophrenia in the Chinese Han population

Choudhury et al. identified FXYD6 as a susceptible gene for schizophrenia in the London and Aberdeen populations. We genotyped D11S1998 and 8 SNPs (rs869789, rs11216567, rs10790212, rs876797, rs4938445, rs497768, rs11216598, rs11605223) in a Chinese sample consisting of 1514 schizophrenia patients and 1514 healthy controls. We also compared the expression levels of FXYD6 in lymphocytes in 86 schizophrenia patients and 94 controls. No association was detected either in D11S1998 or the 8 SNPs. No difference was found in expression level between patients and controls. Our study suggests that FXYD6 does not play a role in schizophrenia in the Chinese Han population.

No association found between the promoter variations of QKI and schizophrenia in the Chinese population.

BACKGROUND Schizophrenia is a chronic psychiatric disorder with a strong genetic component. Several recent published studies have reported that the mRNA expression level of quaking homolog, KH domain RNA binding (QKI) is down regulated in individuals diagnosed with schizophrenia. METHODS We were interested in the genetic variants around the promoter region of QKI and selected seven variants in this region, namely rs4263561, rs3904720, rs387504, rs3763197, rs7772756, rs7758706 and rs4709716. For the study we recruited 288 individuals diagnosed with schizophrenia and 288 control subjects. All the recruits were from Shanghai and were Han Chinese in origin. RESULTS No individual SNP nor any haplotype was found to be associated with schizophrenia. CONCLUSIONS These results suggest that the variants within the promoter region of QKI gene are unlikely to play a major role in susceptibility to schizophrenia in the Chinese population.

Association and expression studies of glutamate-cysteine ligase modifier (GCLM) and schizophrenia in the Chinese Han population.

Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Institutes of Biomedical Sciences, Fudan University, Shanghai Institute of Mental Health, Institute of Neuropsychiatric Science and Systems Biological Medicine, Changning Institute of Mental Health, the Bio-X Center Hospital and Institute for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China Correspondence to Yongyong Shi, Institute of Neuropsychiatric Science and Systems Biological Medicine, Changning Institute of Mental Health, the Bio-X Center Hospital, 299 XieHe Road, Shanghai 200042, PR China Tel/fax: + 86 21 62822491; e-mail: shiyongyong@gmail.com or Lin He, Institutes of Biomedical Sciences, Fudan University, 130 Dongan Road, Shanghai 200032, PR China Tel: + 86 21 54237620; fax: + 86 21 54237632; e-mail: helinhelin@gmail.com

An association study of the SLC26A4 gene in children with mental retardation

It is generally considered that iodine deficiency is the single most common cause of preventable mental retardation (MR) and brain damage. The SLC26A4 gene is expressed at the apical surface of thyrocytes and its product forms an efficient iodide-trapping mechanism. To investigate whether variability in the SLC26A4 gene influences the risk of iodine-deficiency based MR, we undertook an association study between SLC26A4 and MR. Participants were recruited from a relatively isolated and traditionally iodine-deficient region with a high prevalence of MR. The SNPs we selected from the dbSNP and HapMap were identified using ARMS-PCR and sequencing methods. Singular-locus and haplotype association analysis indicated no association between the SLC26A4 gene and MR (p>0.05). The negative results suggest that the SLC26A4 gene has no measurable impact on iodine-deficiency based MR. In view of the characteristics of our samples, our study may provide a good reference for research into the transport features of pendrin in the thyrocyte apical surface.