Biomedical subjects

Xiangning Chen

Publications and source records attributed to Xiangning Chen.

10 recordsLinked to original sources

PubMed2007

Association between the 5q31.1 gene neurogenin1 and schizophrenia.

Multiple lines of evidence suggest that schizophrenia results from aberrant neurodevelopment. The neurogenin1 gene (neurog1) consists of a single 1,666 bp exon that encodes a basic helix-loop-helix (bHLH) transcription factor that causes neuronal differentiation and induces cortical and glutamatergic differentiation programs. Because of its function and its location in 5q31.1, which has been linked to schizophrenia in multiple samples, we tested it for association with the disorder. We sequenced neurog1 in 25 affected subjects from the Irish Study of High-Density Schizophrenia Families. We observed a 5'-UTR SNP at position -60, already present in databases as rs8192558, and tested it along with rs2344485, rs8192559, and rs2344484. Narrow, intermediate, and broad diagnostic definitions were used. The major alleles of rs8192558 and rs2344484 were over-transmitted to affected subjects using both Pedigree Disequilibrium Test (PDT) (0.01 < or = P < or = 0.06) and FBAT (0.02 < or = P < or = 0.07). A haplotype consisting of the major alleles of all four SNPs was significantly over-transmitted in FBAT to the broad definition (P = 0.049), with trend significance to the narrow and intermediate definitions, and with trend significance in PDT. In confirmatory tests using 657 cases and 411 controls, this haplotype was slightly but not significantly over-represented in cases (81% vs. 77%, P = 0.21). These results, along with a priori evidence for the involvement of neurog1 in neurodevelopment, suggest that variants in neurog1 might have a small effect on susceptibility to schizophrenia. This gene should be tested in additional and larger samples.

Basic Helix-Loop-Helix Proteins↗

PubMed2006

Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia.

Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density Schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes.

Chromosomes, Human, Pair 5↗

PubMed2006

The mu-opioid receptor gene and smoking initiation and nicotine dependence.

The gene encoding the mu-opioid receptor (OPRM1) is reported to be associated with a range of substance dependence. Experiments in knockout mice indicate that the mu-opioid receptor may mediate reinforcing effects of nicotine. In humans, opioid antagonist naltrexone may reduce the reinforcing effects of tobacco smoking. Additionally, the OPRM1 gene is located in a region showing linkage to nicotine dependence. The OPRM1 is thus a plausible candidate gene for smoking behavior. To investigate whether OPRM1 contributes to the susceptibility of smoking initiation and nicotine dependence, we genotyped 11 SNPs in the gene for 688 Caucasian subjects of lifetime smokers and nonsmokers. Three SNPs showed nominal significance for smoking initiation and one reached significance for nicotine dependence. The global test for three-marker (rs9479757-rs2075572-rs10485057) haplotypes was significant for smoking initiation (p = 0.0022). The same three-marker haplotype test was marginal (p = 0.0514) for nicotine dependence. These results suggest that OPRM1 may be involved in smoking initiation and nicotine dependence.

Journal Article↗

PubMed2006

Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples.

BACKGROUND: Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. METHODS: In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). RESULTS: The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. CONCLUSIONS: Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Case-Control Studies↗

PubMed2006

Association of the phosphatase and tensin homolog gene (PTEN) with smoking initiation and nicotine dependence.

Since PTEN (phosphatase and tensin homolog) has elevated expression in rat brain (amygdala) after chronic administration of nicotine and the PTEN gene is located in the vicinity of the chromosome 10q23 linkage peak in a genome-scan study of nicotine dependence, PTEN seems a plausible candidate gene for smoking behavior. To test this hypothesis, we use a three-group case-control design and genotype five SNPs in the PTEN gene. We compare allele and genotype frequencies between the smokers and nonsmokers and between the low nicotine dependent and high nicotine dependent subjects. Three SNPs in the PTEN gene are significantly associated with smoking initiation (rs1234221, P = 0.0311; rs1234213, P = 0.0002; and rs2735343, P = 0.0028). Rs1234213 also shows association with nicotine dependence (P = 0.0278). Haplotype analyses indicate that a major haplotype, 1-1-2-2-1 for rs1234221-rs2299939-rs1234213-rs2735343-rs70184, is associated with smoking initiation. A minor haplotype (about 3%), 1-2-2-2-1 for the same five SNPs, is observed only in the high nicotine dependence group. These results suggest that the PTEN gene may be involved in the etiology of both smoking initiation and nicotine dependence.

Alleles↗

PubMed2004

Association study of the Epac gene and tobacco smoking and nicotine dependence.

Exchange protein directly activated by cAMP (Epac) has been shown to increase its expression in rat prefrontal cortex after self-administration of nicotine. [Konu et al. 2001: Brain Res 909:194-203]. We investigated the role of the human ortholog of Epac in tobacco smoking and nicotine dependence (ND). Using a case-control design, we typed 5 SNPs in this gene in 688 subjects, of whom 244 were non-smokers, 215 were Low-ND smokers, and 229 were High-ND smokers. We tested allele and genotype association to smoking initiation (SI) and progression to ND. Three of the five typed SNPs showed modest allele association with progression to ND. Weak association with SI was also observed for one SNP. Considering the function of the gene in cellular signal transduction pathway, its elevated expression after nicotine self-administration, and multiple markers association with both SI and progression to ND, it is plausible to suggest that variants in Epac contribute to the liability to ND.

Alleles↗

PubMed2004

Regulator of G-protein signaling 4 (RGS4) gene is associated with schizophrenia in Irish high density families.

The regulator of the G-protein signaling 4 (RGS4) gene was shown to have a different expression pattern in schizophrenia patients in a microarray study. A family-based study subsequently implicated the association of this gene with schizophrenia. We replicated the study with our sample from the Irish Study of High Density Schizophrenia Families (ISHDSF). Single marker transmission disequilibrium tests (TDT) for the four core SNPs showed modest association for SNP 18 (using a narrow diagnostic approach with FBAT P = 0.044; with PDT P = 0.0073) and a trend for SNP 4 (with FBAT P = 0.1098; with PDT P = 0.0249). For SNP 1 and 7, alleles overtransmitted to affected subjects were the same as previously reported. Haplotype analyses suggested that haplotype G-G-G for SNP1-4-18, which is the most abundant haplotype (42.3%) in the Irish families, was associated with the disease (narrow diagnosis, FBAT P = 0.0061, PDT P = 0.0498). This was the same haplotype implicated in the original study. While P values were not corrected for multiple testing because of the clear prior hypothesis, these results could be interpreted as supporting evidence for the association between RGS4 and schizophrenia.

Alleles↗

PubMed2004

A multiplexing single nucleotide polymorphism typing method based on restriction-enzyme-mediated single-base extension and capillary electrophoresis.

Millions of single nucleotide polymorphisms (SNPs) have been identified in recent years. This provides a great opportunity for large-scale association and population studies. However, many high-throughput SNP typing techniques require expensive and dedicated instruments, which render them out of reach for many laboratories. To meet the need of these laboratories, we here report a method that uses widely available DNA sequencer for SNP typing. This method uses a type II restriction enzyme to create extendable ends at target polymorphic sites and uses single-base extension (SBE) to discriminate alleles. In this design, a restriction site is engineered in one of the two polymerase chain reaction (PCR) primers so that the restriction endonuclease cuts immediately upstream of the targeted SNP site. The digestion of the PCR products generates a 5'-overhang structure at the targeted polymorphic site. This 5'-overhang structure then serves as a template for SBE reaction to generate allele-specific products using fluorescent dye-terminator nucleotides. Following the SBE, the allele-specific products with different sizes can be resolved by DNA sequencers. Through primer design, we can create a series of PCR products that vary in size and contain only one restriction enzyme recognition site. This allows us to load many PCR products in a single capillary/lane. This method, restriction-enzyme-mediated single-base extension, is demonstrated by typing multiple SNPs simultaneously for 44 DNA samples. By multiplexing PCR and pooling multiplexed reactions together, this method has the potential to score 50-100 SNPs/capillary/run if the sizes of PCR products are arranged at every 5-10 bases from 100 to 600 base range.

Alkaline Phosphatase↗

PubMed2003

Fluorescence polarization for single nucleotide polymorphism genotyping.

Single nucleotide polymorphisms (SNPs) are the most abundant variations in the human genome and have become the primary markers for genetic studies for mapping and identifying susceptible genes for complex diseases. Methods that genotype SNPs quickly and economically are of high values for these studies because they require a large amount of genotyping. Fluorescence polarization (FP) is a robust technique that can detect products without separation and purification and it has been applied for SNP genotyping. In this article the applications of FP in SNP genotyping are reviewed and one of the methods, the FP-TDI assay, is discussed in details. It is hoped that readers could get useful information for the applications of FP in SNP genotyping and some insights of the FP-TDI assay.

Animals↗

PubMed2003

Detection of single nucleotide polymorphisms.

Single nucleotide polymorphism (SNP) detection technologies are used to scan for new polymorphisms and to determine the allele(s) of a known polymorphism in target sequences. SNP detection technologies have evolved from labor intensive, time consuming, and expensive processes to some of the most highly automated, efficient, and relatively inexpensive methods. Driven by the Human Genome Project, these technologies are now maturing and robust strategies are found in both SNP discovery and genotyping areas. The nearly completed human genome sequence provides the reference against which all other sequencing data can be compared. Global SNP discovery is therefore only limited by the amount of funding available for the activity. Local, target, SNP discovery relies mostly on direct DNA sequencing or on denaturing high performance liquid chromatography (dHPLC). The number of SNP genotyping methods has exploded in recent years and many robust methods are currently available. The demand for SNP genotyping is great, however, and no one method is able to meet the needs of all studies using SNPs. Despite the considerable gains over the last decade, new approaches must be developed to lower the cost and increase the speed of SNP detection.

Alleles↗