Positive association of the human GABA-A-receptor beta 2 subunit gene haplotype with schizophrenia in the Chinese Han population

A converging body of evidence implicates the gamma-amino butyric acid neurotransmitter system in the pathogenesis of schizophrenia. Recently, Lo et al. reported strong positive association between schizophrenia and GABRB2, demonstrated by single markers and haplotypes of five markers in introns of GABRB2, rs6556547, rs1816071, rs194072, rs252944, and rs187269. To validate this linkage disequilibrium report, we genotyped these five SNPs and additional rs1816072 in 352 Chinese Han family trios. Though we failed to detect any positive results in single markers, we did find a significant haplotypic association (global p = 0.00157-0.00588) which had not been identified in Lo's study. Our data indicated that the haplotype 'GACTCT' (p = 0.00215, frequency = 53.6%) was overtransmitted which suggests that GABRB2 is in linkage disequilibrium with schizophrenia in the Chinese Han population. The difference between the two studies may be due to the respective analytic power of the two designs. These two independent studies highlighting linkage disequilibrium support the potential involvement of GABRB2 or a nearby gene in the genetic etiology of schizophrenia.     

No association between the PTGS2/PLA2G4A locus and schizophrenia in a Chinese population

The present study was undertaken to replicate an association between the PTGS2/PLA2G4A locus and schizophrenia among a Chinese population. We recruited 168 Chinese parent-offspring trios of Han descent, consisting of fathers, mothers and affected offspring with schizophrenia. Of 3 informative SNPs genotyped, no one showed allelic association with schizophrenia; the haplotype analysis also failed to capture a haplotypic association with the illness. Because the frequencies of alleles and genotypes of SNPs analyzed differ in the Chinese population as compared with a British population that initially showed the genetic association between the PTGS2/PLA2G4A locus and schizophrenia, the ethnic background may be a major reason for poor replication of the initial finding.     

Association between promoter variants of interleukin-18 and schizophrenia in a Han Chinese population

An increasing amount of evidence suggests that interleukin-18 (IL-18) plays a pivotal role in the pathophysiology of schizophrenia. However, association between single nucleotide polymorphism of IL-18 and the risk of schizophrenia has not been clarified. This study examined whether two promoter polymorphisms -137 G/C (rs187238) and -607 C/A (rs1946518) of IL-18 were associated with schizophrenia and six clinical symptoms (disorder of perception, thought disorder, disturbance of emotion, disorder of behavior and volition, suicide action, and aggressive action) to provide data for screening high-risk Han Chinese individuals. Three hundred seventy-two schizophrenic patients and 353 healthy controls from a Han Chinese population were examined to assess their genotype and allele frequencies of the two promoter polymorphisms of IL-18. The genotype distributions in both patients and controls were within Hardy-Weinberg equilibrium. No significant differences were observed in the genotype or the allele frequencies of the two single-nucleotide polymorphisms between patients and controls. However, genotype frequencies of -607 C/A showed significant differences between patients and controls in the appearance of perception disorder (χ2 = 6.153, p = 0.046). A significant difference was detected in -137 G/C between patients and controls in the appearance of aggressive action (χ2 = 3.909, p = 0.048). In conclusion, IL-18 gene promoter polymorphisms may not contribute to the susceptibility of schizophrenia in a Han Chinese population, but two single-nucleotide polymorphisms, -137 G/C and -607 C/A, may play a role in the development of perception disorder and aggressive action, respectively.     

The genetic association between osteoprotegerin gene polymorphisms and fracture risk in Chinese Han population

This article put the genetic association exploration of osteoprotegerin (OPG) gene polymorphisms in promoter region (A-163G, T-245G) and fracture risk first and hoped to explain the ethology of fracture. The genotyping of OPG gene polymorphisms was conducted with the method of polymerase chain reaction-restriction fragment length polymorphism in 125 fracture patients and 138 relative controls. The genotype frequencies of selected controls based on OPG gene polymorphisms were checked by the χ² test whether conformed to Hardy–Weinberg equilibrium (HWE). The relative risk was represented with odds ratio (OR) and 95% confidence interval (95% CI) between gene polymorphism and disease. The linkage disequilibrium (LD) and haplotype were also analyzed. The genotypes distributions of selected controls in OPG polymorphisms conformed to HWE. The G allele of A-163G polymorphism carriers had the tendency to suffer from fracture in the same condition, compared with A allele carriers (OR = 1.63, 95% CI = 1.04–2.55). TG and TG/GG genotypes of OPG T-245G polymorphism also showed the increased risk of fracture development, but not TT genotype (OR = 2.22, 95% CI = 1.15–4.28; OR = 2.45, 95% CI = 1.28–4.68). Likely, the mutant allele G had an abnormally higher frequency in cases than controls (14.00% and 6.16%). These two polymorphisms existed the LD and the haplotype G _-163–G _-245 obviously increased the risk of fracture. OPG A-163G, T-245G polymorphisms were associated with the onset of fracture and both the independent risk factors.     

Genome-wide association study of treatment refractory schizophrenia in Han Chinese

We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04 × 10(-7)) and rs11265461 (P = 1.94 × 10(-7)) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94 × 10(-6)) and rs230529 (P = 1.74 × 10(-7)) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05 × 10(-5)) and rs3827219 (P = 1.66 × 10(-5)) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87 × 10(-5)) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85 × 10(-6)). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.     

Positive association of CC2D1A and CC2D2A gene haplotypes with mental retardation in a Han Chinese population

The CC2D1A and CC2D2A genes are involved in Ca(2+)-regulated signaling pathways and have recently been implicated in the etiology of mental retardation (MR). The aim of this study was to investigate whether CC2D1A and CC2D2A polymorphisms are associated with susceptibility to MR in a Han Chinese population using a family based association approach. The sample included 172 trios (parents and offspring), and all subjects were genotyped for several single-nucleotide polymorphisms covering CC2D1A and CC2D2A. Linkage disequilibrium (LD) analysis revealed that the rs6511901 and rs10410239 polymorphisms of CC2D1A were in strong LD (D'=0.865), and haplotype analysis showed evidence for over-transmission from parents to MR offspring (p=0.0009). The LD analysis also revealed that CC2D2A single-nucleotide polymorphisms rs10025837, rs13116304, and rs7661102 were in strong LD (D'=0.848), and haplotype analysis showed significant transmission disequilibrium (p=0.0004). The results suggest the involvement of CC2D1A and CC2D2A in MR in the Han Chinese population, and some specific haplotypes may be susceptible or protective.     

Evaluation of the association between the AC3 genetic polymorphisms and obesity in a Chinese Han population

Background

AC3 is one of adenylyl cyclase isoforms involved in cAMP and insulin signaling pathway. Recent reports have demonstrated that the AC3 genetic polymorphisms are associated with obesity in a Swedish population. AC3 knock out mice exhibit obese when they age. These findings suggest that AC3 plays an important role in the regulation of body weight.

Methodology/Principal Findings

In the present study, we evaluated the association between the AC3 genetic polymorphisms and obesity in a Han Chinese population. A total of 2580 adults, including 1490 lean (BMI = 18.5–23.9), 677 overweight (BMI 24.0–27.9) and 413 obese (BMI ≥28.0) subjects were genotyped for 5 TagSNPs in the AC3 gene. Single maker association analyses indicated that SNP rs753529 was significantly associated with BMI in obese subjects (P = 0.022, OR = 0.775 95%CI = 0.623–0.963), but not in overweight subjects (P = 0.818). Multiple maker association analyses showed that the haplotype (G-G-G) constructed with SNPs rs1127568, rs7604576 and rs753529 was significantly associated with obesity (P = 0.029). Further genotyping of SNP rs753529 in 816 children, including 361 overweight subjects (BMI>P₈₀) and 455 controls (BMI = P_20–50) were performed, and no significant association with BMI was found. All tests were adjusted for age, sex, physical activity index, household income and/or diet expenses.

Conclusions

The present study provides replication evidence that the AC3 genetic polymorphisms are associated with decreased risk of obesity among adults but not in children in a Chinese Han population. The data also suggest that the AC3 genetic effects on BMI may have interaction with the factors related to ageing and environment.     

No association between the PPARG gene and schizophrenia in a British population

It has consistently been reported that patients with schizophrenia have an increased risk of type-2 diabetes. To investigate a genetic link between these two diseases, the combined effects of the PLA2G4A, PTGS2 and PPARG genes were tested among 221 British nuclear families consisting of fathers, mothers and affected offspring with schizophrenia. A total of 10 single nucleotide polymorphisms (SNPs) were tested and the likelihood-based association analysis for nuclear families was used to analyse the genotyping data. Eight SNPs detected across the PPARG gene did not show allelic association with schizophrenia; a weak association was detected at rs2745557 in the PTGS2 locus (χ²=4.19, p=0.041) and rs10798059 in the PLA2G4A locus (χ²=4.28, p=0.039) but these associations did not survive after 10,000 permutations to correct the p-value (global p=0.246). The gene–gene interaction test did not show any evidence of either cis-phase interactions for the PLA2G4A and PTGS2 combinations or a trans-phase interaction for the PLA2G4A and PPARG combinations. The PPARG gene has been reported to be strongly associated with type-2 diabetes, but the present study did not support the hypothesis that the PPARG gene may also play an important role in the development of schizophrenia.     

Lack of association between polymorphisms in the P2X7 gene and tuberculosis in a Chinese Han population

Several studies have suggested that genetic factors may affect the susceptibility of a population to tuberculosis, and it has been found that P2X7 is linked to an increased risk for tuberculosis in some West African, Southeast Asian, North American, and North European populations. To explore the potential role of P2X7 in the susceptibility to tuberculosis among members of the Chinese Han population, we evaluated the association of the 1513A→C and −762T→C polymorphisms in P2X7 with the risk for tuberculosis. PCR amplification of genomic DNA was followed by restriction fragment length polymorphism analysis, and allele-specific PCR was used. We found no significant differences in the genotypic and allelic frequencies of 1513A→C polymorphisms in 96 patients with tuberculosis compared with 384 control subjects [ P =0.856 and 0.316, respectively; odds ratio (OR) for the C allele=0.976; 95% confidence interval (CI)=0.755–1.262]. Similarly, no significant association was found between the −762T→C polymorphism and tuberculosis ( P =0.102 and 0.095 for the patients and controls, respectively; OR for the C allele=0.924; 95% CI=0.847–1.010). Thus, our analysis of P2X7 showed that the 1513A→C and −762T→C polymorphisms did not appear to be associated with the susceptibility of the Chinese Han population to tuberculosis.     

Dermatoglyphic changes during the population admixture between Kam and Han Chinese

Genetic studies and gene localization for human dermatoglyphs are currently ongoing. However, the inheritance modes of various genetic traits are not well understood because of the complexity of dermatoglyph genetics. The study of admixed populations can contribute to the understanding of population genetic traits of dermatoglyphs. Here, we present the dermatoglyphic characteristics of Kam and Liujia Han, and the admixed population consisting of these two parent populations.The characteristics of the admixed population do not always fall in the same ranges as the parent population characters but do seem to be biased to Kam or Liujia parent populations, depending on sex and ethnicity of parents. The total frequencies of different fingerprint types do not differ among these populations, but several of the quantitative traits and the palm true pattern frequencies do significantly differ between admixed and parent populations. The simple arch fingerprint frequency decreases significantly in the admixed population in comparison with parent populations while both simple whorl fingerprint frequency and finger ridge counts increase significantly. True pattern frequency of the span area of interdigital III and IV areas on right hands and the radial-loop frequency of the right index fingers in the admixed populations are consistent with their matrilineal population. These dermatoglyphic changes may result from increased heterozygosity in the admixed population. The genetic modes of these changes may be relatively simple and will be useful for future dermatoglyph genetic studies.      

Interaction between hypertension and HSP70 variants increase the risk of cerebral ischemia in Chinese Han population: An association study

Cerebral infarction has become one of the leading diseases and a major mortality factor around the world. Atherosclerosis is recognized as one of the important causes of ischemic stroke. Recently, accumulating evidences have indicated that the anti-inflammatory and anti-apoptotic functions of the HSP70 family play an important role in cerebral ischemia. However, the association between HSP70 SNPs and ischemic stroke was also not well established. We chose 101 cases of cerebral ischemia and 100 healthy people from the Chinese Han population as our study subjects, and PCR-RFLP was employed to analyze HSP70 polymorphisms: HSP70-1+190G/C, HSP70-2+1267A/G and HSP70-hom+2437T/C. There were no significant differences in + 1267A/G allele or genotype frequencies between patients with stroke and healthy controls. However, genotypes of + 190CG and + 2437TT were differentially distributed between the patients and controls. A significant difference of T allele distribution in the HSP70-hom+2437T/C site was observed. Logistic regression analysis indicated that genotypes of + 190CG, + 2437TT and T allele in HSP70-hom were risk factors of ischemic stroke. Moreover, the study has formulated that the interactions between hypertension and + 190CG or + 2437TT may increase the risks of ischemic stroke. The results from this study have suggested a clinical indicator for assessing the possibilities of cerebral stroke, and supply basis to clinicians to give precaution to people who are at risk of stroke.     

Replication of the association of a MET variant with autism in a Chinese Han population

Background

Autism is a common, severe and highly heritable neurodevelopmental disorder in children, affecting up to 100 children per 10,000. The MET gene has been regarded as a promising candidate gene for this disorder because it is located within a replicated linkage interval, is involved in pathways affecting the development of the cerebral cortex and cerebellum in ways relevant to autism patients, and has shown significant association signals in previous studies.

Principal Findings

Here, we present new ASD patient and control samples from Heilongjiang, China and use them in a case-control and family-based replication study of two MET variants. One SNP, rs38845, was successfully replicated in a case-control association study, but failed to replicate in a family-based study, possibly due to small sample size. The other SNP, rs1858830, failed to replicate in both case-control and family-based studies.

Conclusions

This is the first attempt to replicate associations in Chinese autism samples, and our result provides evidence that MET variants may be relevant to autism susceptibility in the Chinese Han population.     

IL-28B genetic variant is associated with the risk of schizophrenia in the Chinese Han population

Schizophrenia is a severe psychiatric disorder. Although its exact cause is unknown, it is widely accepted that environmental factors and genes integrate in the pathogenesis of schizophrenia. 19q13, which contains IL-28B, is a newly identified potential susceptibility locus. IL-28B is a cytokine that functionally has anti-viral activity, but, structurally, is related to the interleukin-10 family. Both virus infection and cytokine changes have been documented in schizophrenia. We selected the single-nucleotide polymorphism rs8099917, which is associated with IL-28B gene expression, to study its relationship to the susceptibility to schizophrenia. A total of 256 Chinese patients with schizophrenia and 329 healthy controls were studied. Both genotype and allele frequencies showed significant differences between patients and normal subjects (p=0.03 and p=0.04, respectively). Our study suggested that the frequency of allele T was a risk factor for the susceptibility of schizophrenia (odds ratio [OR]=1.76, 95% confidence interval [CI]=1.03-3.03). When all subjects were grouped by symptoms, both the genotype and the allele frequency were associated with patients having disorganized speech (genotype: χ(2)=5.75, p=0.02; allele: χ(2)=5.41, p=0.02, OR=3.67, 95% CI=1.14-11.82) and negative symptoms (genotype: χ(2)=5.09, p=0.02; allele: χ(2)=4.80, p=0.03, OR=1.95, 95% CI=1.06-3.56) as well as cognitive symptoms (genotype: χ(2)=5.97, p=0.02; allele: χ(2)=5.53, p=0.02, OR=2.04, 95% CI=1.11-3.74). The results in this study may lead to a better understanding of the etiology of schizophrenia.     

Novel association of a PROC variant with ischemic stroke in a Chinese Han population

Protein C (PC) is a well-characterized anticoagulant enzyme. However, the association between PC and ischemic stroke (IS) remains controversial. The aim of the present study was to investigate whether any genetic variant in the human protein C gene (PROC) was associated with susceptibility to IS in the Chinese Han population. All exons and the 5′- and 3′-untranslated regions of PROC were initially sequenced to identify informative variants. Potential abnormal variants were analyzed in a population of 788 IS patients and 1,200 healthy controls. The analysis was stratified by stroke etiology, and the results were replicated in 262 IS patients and 288 healthy controls. Finally, functional studies were performed to evaluate the effects of the variant. A three-nucleotide duplication/deletion variant (c.574_576del) was identified and found to be significantly associated with IS (OR 2.56, 95 % CI 1.45-4.52, P = 0.001). Stratification by stroke etiology after adjustment for IS risk factors showed that this association persisted in the lacunar and cardioembolic subtypes (P < 0.001 and P = 0.008, respectively) but not in the atherothrombotic and undetermined subtypes (P = 0.070 and P = 0.998, respectively). The functional studies showed a significant difference in the anticoagulant activity of PC in c.574_576del carriers and non-carriers (P < 0.001). Our results suggested that the novel PROC c.574_576del variant is a possible genetic determinant of an increased risk of IS and diminished anticoagulant activity of PC.     

Genetic association between IL-17F gene polymorphisms and the pathogenesis of Graves' Disease in the Han Chinese population

Background

Graves' Disease (GD) is a common and complex disorder, with a strong hereditary component. IL-17F is a potent cytokine and a potential contributor to the etiology of various human autoimmune diseases. In the present study, we focused on the relationship between polymorphisms in the IL-17F gene and GD susceptibility through a case–control association study in two independent Chinese cohorts.

Methods

Our pilot study was performed on a cohort from Shanghai, which included 757 GD patients and 741 healthy controls. Our replication cohort was from Xiamen, consisting of 434 GD patients and 420 healthy controls. We selected four tag SNPs (rs763780, rs2397084, rs9463772 and rs761167) within the IL-17F gene to conduct a genotyping analysis.

Results

In the Shanghai cohort, the rs9463772 polymorphism showed a significant association with GD and Graves' Disease-associated Ophthalmopathy (GO) patients (P_allele = 7 × 10^− 5 and 7.4 × 10^− 3 for GD and GO patients, respectively). The rs763780 polymorphism was found to have only a difference in genotype distribution between GD individuals and healthy controls (P = 0.017). In the replication study, we confirmed the association between the rs9463772 polymorphism and GD susceptibility. Haplotype analysis showed that the haplotype of the four SNPs (GCTT) was associated with a significant risk of GD in the Shanghai cohort (P = 7.9 × 10^− 3).

Conclusion

Our results suggest that polymorphisms in the IL-17F gene increase the risk of Graves' Disease and that IL-17F is therefore a good candidate gene for Graves' Disease prediction in the Han Chinese population.