A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population

The FXYD domain containing ion transport regulator 6 (FXYD6) gene is located within a region of chromosome 11 (11q23.3) that has been shown by a number of genome scans to be one of the most well-established linkages to schizophrenia. FXYD6 encodes the protein phosphohippolin, which is primarily expressed in the brain. Phosphohippolin modulates the kinetic activity of Na,K-ATPase and has long-term physiological importance in maintaining cation homeostasis. A recent study reported that FXYD6 was associated with schizophrenia in the United Kingdom samples. Applying the gene-based association concept, we carried out an association study regarding FXYD6 and schizophrenia in a Japanese population, with a sample consisting of 2026 subjects (906 schizophrenics and 1120 controls). After linkage disequilibrium analysis, 23 single nucleotide polymorphisms (SNPs) were genotyped using 5'-exonuclease allelic discrimination assay. We found a significant association of two SNPs (rs11216573; genotypic P value: 0.022 and rs555577; genotypic P value: 0.026, allelic P value: 0.011, uncorrected). Nominal P values did not survive correction for multiple testing (rs11216573; genotypic P value: 0.47 and rs555577; genotypic P value: 0.55, allelic P value: 0.24, after SNPSpD correction). No association was observed between schizophrenia patients and controls in allelic, genotypic and haplotypic analyses. Our findings suggest that FXYD6 is unlikely to be related to the development of schizophrenia in a Japanese population.     

ESR1基因单核苷酸多态性及单倍型与精神分裂症的关联研究

目的 探索雌激素受体1 (estrogen receptor 1,ESR1)基因rs2234693、rs9340799和rs3798759位点单核苷酸多念性(single nucleotide polymorphisms,SNPs)及其单倍型与精神分裂症(schizophrenia,SZ)发病之间的相关性.方法 应用聚合酶链反应-限制性片段长度多态性技术对333例SZ患者和315名正常对照rs2234693、rs9340799和rs3798759位点进行基因分型,应用x2检验对SZ组和对照组等位基因、基因型和单倍型频率进行分析.结果 rs2234693、rs9340799位点两组间基因型频率及等位基因分布差异均无统计学意义(P＞0.05).SZ组rs3798759位点GG基因型频率及G等位基因频率均高于健康对照组(P＜0.01).性别分层分析提示,女性SZ患者rs3798759位点TG、GG基因型频率及G等位基因频率均高于健康女性(P＜0.05).单倍型C-A-G和C-G-G在SZ组的分布频率高于对照组(P＜0.05).结论 rs3798759位点突变可能为女性精神分裂症发生的风险因子,C-A-G和C-G-G单倍型可能为精神分裂症的遗传风险单倍型.     

Association of PRKCH gene with lacunar infarction in a local Chinese Han population

Recent evidence indicated that the PRKCH gene was a susceptibility gene for lacunar infarction in a Japanese population. The aim of the present study was to explore the association of the gene with lacunar infarction in a population of Chinese Han ancestry. A total of 280 consecutive lacunar infarction patients and 306 unrelated population-based controls that had been matched for age and sex were examined using a case–control design. Two single nucleotide polymorphisms (SNPs) of PRKCH gene (rs3783799 and rs2230500) were genotyped with ligase detection reaction (LDR) and multiplex polymerase chain reaction (PCR). Linkage disequilibrium (LD) and haplotype analysis were also investigated between these two groups. Overall alleles and genotype frequencies were similar between cases and controls. No significant association was detected with the gene polymorphisms mentioned above and lacunar infarction; no significant difference was found with haplotype analysis between these two groups. None of the two SNPs showed significant association with lacunar infarction in the whole subjects before and after adjustment for conventional stroke risk factors (hypertension, diabetes mellitus, and hypercholesterolemia). The frequencies of PRKCH differed largely from those in the Japanese population. The present study suggests that variants in the PRKCH gene are not the risk factors for lacunar infarction in individuals from a small population of Chinese Han ancestry. Population differences in alleles and haplotype frequencies as well as LD structure may contribute to the observed differences between populations.     

No association between the Bcl2-interacting killer (BIK) gene and schizophrenia

The Bcl2-interacting killer (BIK) gene interacts with cellular and viral survival-promoting proteins, such as Bcl-2, to enhance apoptosis. The BIK protein promotes cell death in a manner analogous to Bcl-2-related death-promoting proteins, Bax and Bak. There have been lower Bcl-2 levels and increased Bax/Bcl-2 ratio in the temporal cortex of patients with schizophrenia compared with those in controls. Because the death-promoting activity of BIK was suppressed in the presence of the cellular and viral survival-promoting proteins, the BIK protein is suggested as a likely target for antiapoptotic proteins. The purpose of this study is to investigate the association between genetic variants in the BIK gene and schizophrenia in a large Japanese population (1181 patients with schizophrenia and 1243 healthy controls). We found nominal evidence for association of alleles, rs926328 (χ² = 4.44, p = 0.035, odds ratio = 1.13) and rs2235316 (χ² = 4.41, p = 0.036, odds ratio = 1.13), with schizophrenia. However, these associations were no longer positive after correction for multiple testing (rs926328: corrected p = 0.105, rs2235316: corrected p = 0.108). We conclude that BIK might not play a major role in the susceptibility of schizophrenia in Japanese population.     

Evidence for transmission disequilibrium at the DAOA gene locus in a schizophrenia family sample

Recently, the DAOA gene locus on chromosome 13q32–q34 has been implicated in the etiology of schizophrenia. We genotyped three single-nucleotide polymorphisms (SNPs: rs778294, rs779293 and rs3918342) in this region in 126 Chinese family trios. In this study, we have identified statistically significant transmission disequilibrium in two markers rs778293 (P = 0.01) and rs3918342 (P = 0.02), and a highly significant under-transmission between haplotype CAT (P = 0.0005) and schizophrenia. The results provide further evidence to support that DAOA gene locus is involved in conferring susceptibility to schizophrenia.     

Association study of polymorphisms between DISC1 and schizophrenia in a Korean population

To further clarify schizophrenia (SCZ), disrupted in schizophrenia 1 (DISC1) is a promising candidate gene expressed predominantly within the hippocampus. Several lines of evidence suggest that DISC1 may be involved in susceptibility to SCZ. In this study, we investigated whether genetic polymorphisms in the coding region of DISC1 were associated with several SCZ clinical phenotypes in a Korean population. To examine any association between DISC1 and SCZ, we genotyped three clinical single nucleotide polymorphisms (SNPs) (rs3738401, R264Q; rs3738402, L465L; rs821616, S704C) in the coding region of the DISC1 gene using the Illumina Sentrix Array Matrix chip and direct sequencing in 303 patients with SCZ and 300 healthy controls. Our case-control analysis showed that none of these SNPs was associated with SCZ. In further endophenotype stratification, however, we found a significant association between rs821616 and the poor concentration subgroup of SCZ, determined using the Operational Criteria Checklist (codominant model, p=0.015). Our results suggest that DISC1 may be a susceptibility gene for poor concentration among Korean patients with SCZ.     

精神分裂症与NOS1多态性的关联研究

目的 探讨一氧化氮合酶1(nitric oxide synthase 1,NOS1)基因多态性与精神分裂症易感性的相关性.方法 选取NOS1区域的28个标签单核苷酸多态性(single nucleotide polymorphisms,SNPs)位点,应用Illumina GoldenGate定制芯片对382例汉族精神分裂症患者和448名正常人的DNA进行分型,并分析其与精神分裂症的相关性.结果 单位点分析提示SNP位点rs1520811与精神分裂症存在关联,但是经过Bonferroni多重校正后差异无统计学意义(P＞0.05).单体型分析未发现单体型与精神分裂症的相关性.结论 未证实NOS1为精神分裂症的易感基因.     

The incidence of acute graft-versus-host disease increases with Candida colonization depending the dectin-1 gene status

Dectin-1 plays an important role in antifungal immunity. The dectin-1 Y238X polymorphism, which results in decreased Th17 responses, is associated with increased Candida colonization of stem cell transplantation (SCT) recipients. In this study we found no impact of the polymorphism on the incidence of graft-versus-host disease (GvHD), or on disease-free and overall survival in these SCT recipients. However, patients from patient–donor pairs bearing the wild-type allele who where colonized with Candida had a significant increased incidence of acute GvHD compared to non-colonized patients (OR = 2.6, P = 0.04). The fact that this was not the case in patients from pairs with the Y238X polymorphism (OR = 1.2, ns) suggests that despite increased colonization defective dectin-1 signaling might have prevented an impact of Candida colonization on the incidence of acute GvHD to occur. These are the first human data showing a role for Candida in the pathogenesis of acute GvHD. The mechanism could involve C-type lectin receptor mediated Th17 responses.     

Association between ERAP1 gene polymorphisms and ankylosing spondylitis susceptibility in Han population

Purposes: The present study was designed to investigate the relationship between endoplasmic reticulum amino peptidase 1 (ERAP1) gene polymorphisms and ankylosing spondylitis (AS) in Han population of Shaanxi province. Methods: 100 AS patients and 100 healthy people were enrolled in present study as case and control groups respectively, and the control group was matched with the case group by age and gender. ERAP1 gene rs27434 and rs7711564 polymorphisms were test by TaqMan probe genotyping method. SHEsis software was used to operate linkage disequilibrium (LD) and haplotype analysis between the two single nucleotide polymorphisms (SNPs). χ² test was employed to compare the differences of the genotype, allele and haplotype frequencies between the case and control groups. Relative risk of AS was represented by odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: In ERAP1 rs27434 and rs7711564 polymorphisms, the frequencies of AA and CC genotypes in case group were significantly higher compared to those in control group (P=0.036; P=0.039), and so were the frequencies of A and C alleles (OR=1.589, 95% CI=1.070-2.359, P=0.028; OR=1.535, 95% CI=1.021-2.308, P=0.050). Linkage disequilibrium test and haplotype analysis of the alleles of the two SNPs showed that the frequency of A-C haplotype was higher in case group than that in control group (P=0.005), which indicated that A-C might be the susceptible haplotype to AS. Conclusions: ERAP1 gene rs27434 and rs7711564 polymorphisms may increase the risk of AS.     

Common genetic variations in TPH1/TPH2 genes are not associated with schizophrenia in Japanese population

Alteration of serotonin transmission in the brain of patients with schizophrenia has been reported in postmortem brain studies, cerebrospinal fluid studies, and pharmacological challenges. Although a genetic association of tryptophan hydroxylase isoform 1 (TPH1), the rate-limiting enzyme in serotonin synthesis, with schizophrenia has been suggested by recent systematic meta-analyses, the newly identified neuronal isoform TPH2 is more relevant to the central nervous system and the association of TPH2 gene with schizophrenia has been much less explored. We, therefore, explored the association of TPH2 gene with schizophrenia using a case–control study of 720 Japanese populations and also tried to replicate the association of the TPH1 rs1800532 (A218C) single nucleotide polymorphism (SNP) with schizophrenia. We selected 15 tagging SNPs in the TPH2 gene. We found no significant differences in genotypic distributions (uncorrected P = 0.18–0.98) or allelic frequencies (uncorrected P = 0.18–0.98) of the 15 SNPs between the schizophrenia and control groups. Haplotypes constructed with these SNPs were also not associated with schizophrenia (uncorrected P = 0.12–0.97). The genotypic and allelic distribution of the TPH1 rs1800532 SNP was also not different between the case and control groups in our samples. In addition, a subsequent meta-analysis including our results did not showed a significant association with schizophrenia in Asian populations. Our findings suggest that neither common genetic variations of TPH1 nor TPH2 are likely to contribute to the genetic susceptibility to schizophrenia in Japanese population.     

SORL1 is genetically associated with Alzheimer disease in a Japanese population

A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-?4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.     

RET基因调控区遗传变异与先天性巨结肠患病风险研究

目的先天性巨结肠（HSCR）是一种复杂的先天性疾病,RET是其主要的易感性基因。本研究对RET非编码区单核甘酸多态性（SNP）-5G〉A（rs10900296）,-1A〉C（rs10900297）和intron1 C〉T（rs2435357）进行分型分析,评估RET基因调控区SNPs及单倍型与先天性巨结肠之间的相关性。方法选取115名病例组病人和139名对照组正常人群,应用聚合酶链反应（PCR）技术和直接测序的方法进行基因分型。回归模型中使用OR值和95%置信区间（CI）作为基因型危险性的评价指标。结果 -5G〉A,-1A〉C,intron1C〉T各基因型频率在病例和对照人群的分布具有显著差异。-5 AA（OR=6.26,95%CI=3.62-10.83）,-1 CC（OR=7.54,95%CI=2.06-27.66）和intron1 TT（OR=19.22,95% CI=7.54-48.99）基因型均能显著增加HSCR发病的风险。单倍型A-C-T（OR=6.28,95% CI=3.77-10.46）和双体型A-C-T/A-C-T（OR=13.62,95% CI=3.48-53.30）分析同样表明与HSCR发病风险存在较强的相关性,并呈现出一定的累积效应。结论 RET基因调控区的基因多态性可能与HSCR的发病易感性有关,支持RET通路的常见变异在HSCR的发展过程中起着重要的作用的假设。     

Candidate gene analysis of SPARCL1 gene in patients with multiple sclerosis

Recently, proteomic analysis in cerebrospinal fluid (CSF) from patients with MS identified four proteins which are present in MS but not in normal human CSF, including SPARCL1, an extracellular matrix-associated protein member of the SPARC family. One hundred eighty-six patients with MS and 185 age-matched controls were genotyped for A/G single nucleotide polymorphism (SNP) in exon 1 (rs1049539), C/G SNP in exon 4 (rs1049544), resulting in a substitution of an aspartate with an histidine, and A/G substitution in the exon 5 (rs1130643), leading to the substitution of alanine with threonine. No significant differences in either allelic or genotypic frequency of the three SNPs were found (P>0.05), even in stratifying MS patients according to the course of the disease. Stratifying according to gender, a trend towards a decreased frequency of the C/C genotype of the rs1049544 was observed in male patients as compared with male controls (30.2% versus 44.0%; P=0.217). Despite proteomic studies in CSF from MS patients suggested an important role for SPARCL1 in the development of the disease, SPARCL1 gene does not appear to act as susceptibility factor for MS in the population investigated here. However, the frequency of the C/C genotype of rs1049544 was decreased in male patients, possibly conferring a lower risk of developing MS in male population. Further studies are needed to clarify this issue.     

Lack of replication of a previously reported association between polymorphism in the 3′UTR of the alpha-synuclein gene and Parkinson's disease in Chinese subjects

Recent studies have implicated polymorphisms in the 3′ untranslated region (3′UTR) of the alpha-synuclein (SNCA) gene in the development of Parkinson's disease (PD). Single nucleotide polymorphism (SNP) rs356165 is one of polymorphisms located in the 3′UTR and its association with PD has been reported but remains controversial. Herein, we conducted a case-control study to further evaluate the possible association between SNP rs356165 and PD in Chinese. All subjects (330 PD patients and 300 normal controls) were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No statistically significant difference in genotype frequency between cases and controls was observed (P = 0.863), suggesting no association of SNP rs356165 with PD in our population. Thus, it may be premature to conclude an association between the 3′UTR of the SNCA gene and PD, and this association should be further examined in different ethnic populations.     

Functional variants of the genes involved in neurodevelopment and susceptibility to schizophrenia in an Armenian population

Aberrant neurodevelopment contributes to the etiology of schizophrenia. This study aimed to investigate the potential association of netrin G1 (NTNG1) rs628117 and brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) genetic polymorphisms with susceptibility to schizophrenia. One hundred three Armenian patients with schizophrenia and 105 healthy control subjects were genotyped by polymerase chain reaction with sequence-specific primers. Whereas the NTNG1 rs628117 genotypes were equally distributed in the groups, the carriers of the less common BDNF 66Met allele were overrepresented among patients with schizophrenia when compared with healthy controls (55% vs 35%, odds ratio = 2.28, 95% confidence interval 1.14-1.98, p(corrected) = 0.006). Furthermore, the 66Met/Met genotype correlated with earlier disease onset (p = 0.024). In conclusion, our single-cohort study nominates the BDNF 66Met allele as a risk factor for schizophrenia in an Armenian population. This must be confirmed in other Armenian cohorts.     

Effect of SOX10 gene polymorphism on early onset schizophrenia in Chinese Han population

Schizophrenia is one of highly heritable psychiatric disorders. Patients with early onset schizophrenia tend to have a greater genetic loading and may be an attractive subpopulation for genetics studies. A single nucleotide polymorphism (SNP) rs139887 in sex-determining region Y-box 10 (SOX10), a candidate gene for schizophrenia, was suggested to be associated with schizophrenia although inconsistent results had been reported. The aim of this study was to evaluate the association between SOX10 rs139887 polymorphism and schizophrenia using an early onset sample in the Chinese Han population. A total of 321 schizophrenic patients with onset before age 18 and 400 healthy controls were recruited for association study. In addition, two populations involved in three studies were selected for meta-analysis to determine the effect of rs139887 on schizophrenia. Our association study results showed that the allele and genotype frequencies were significantly different between schizophrenic patients and controls (P=0.013 and P=0.034, respectively). Interestingly, a significant association in allele and genotype frequencies were found in male patients (P=0.017 and P=0.045, respectively), but not female patients. Moreover, the C/C genotype had a significant association with an earlier age of onset in male schizophrenic patients (Kaplan-Meier log-rank test P=0.029), but not in female patients (Kaplan-Meier log-rank test P=0.876). The meta-analysis result showed the same C allele was significantly associated with schizophrenia (P=0.007). In conclusion, the SOX10 rs139887 polymorphism was related to the development of schizophrenia in a gender-specific manner, and may be a significant genetic marker for managing subgroups and etiological clues in schizophrenia.     

High-resolution SNP map of ASPN, a susceptibility gene for osteoarthritis

Osteoarthritis (OA) is a very common bone and joint disease characterized by breakdown of cartilage in the joint. We recently found that an aspartic-acid repeat polymorphism of the asporin gene (ASPN) on chromosome 9 is associated with susceptibility to OA in Japanese. We provide here a high-resolution single nucleotide polymorphism (SNP) map within a 33.4-kb genomic region containing ASPN. A total of 19 SNPs were isolated from the region by systematic screening using 48 Japanese patients with OA: 7 SNPs in the 5 flanking region, 8 in introns, and 4 in the 3 untranslated region. Nine SNPs were novel. This high-resolution SNP map will be a useful resource for analyzing genes associated with OA and other bone and joint diseases.     

Renalase gene is a novel susceptibility gene for essential hypertension: a two-stage association study in northern Han Chinese population

Renalase, a novel flavin adenine dinucleotide-dependent amine oxidase, is secreted by the kidney, degrades circulating catecholamines, and modulates cardiac function and systemic blood pressure (BP). Its discovery may provide novel insights into the mechanisms of BP regulation and the pathogenesis of essential hypertension (EH). We designed a two-stage case-control study to investigate whether the renalase gene harbored any genetic variants associated with EH in the northern Han Chinese population. From the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA in China), 1,317 hypertensive cases and 1,269 normotensive controls were recruited. These total 2,586 subjects were taken as the main study population in this study. In stage 1, all the eight selected single nucleotide polymorphisms (SNPs) of the renalase gene were genotyped and tested within a subsample (503 cases and 490 controls) of the main study population. By single locus analyses, three SNPs, rs2576178, rs2296545, and rs2114406, showed significant associations with EH (P < 0.05). In stage 2, these three SNPs were genotyped on the remaining individuals and analyzed using all the individuals. After Bonferroni correction for multiple comparisons, the associations of rs2576178 and rs2296545 with EH were still significant in stage 2. The cases had higher frequencies of rs2576178 G allele and rs2296545 C allele than the controls (0.55 versus 0.49, P < 0.0001; 0.61 versus 0.55, P < 0.0001). Particularly, under the codominant model, the adjusted odds ratios for rs2576178 GG genotype and rs2296545 CC genotype were 1.58 (95% CI, 1.25 to 2.00; P = 0.0002) and 1.61 (95% CI, 1.26 to 2.04; P = 0.0002), respectively. We also found risk-associated haplotypes and diplotypes, which further confirmed the significant association between the renalase gene and EH. These findings may provide novel genetic susceptibility markers for EH and lead to a better understanding of EH pathophysiology. In addition, further replications in other populations and functional studies would be warranted.

Association analysis of the DISC1 gene with schizophrenia in the Japanese population and DISC1 immunoreactivity in the postmortem brain

The Disrupted-in-Schizophrenia 1 (DISC1) gene plays a role in the regulation of neural development. Previous evidence from genetic association and biological studies implicates the DISC1 gene as having a role in the pathophysiology of schizophrenia. In the present study, we explored the association between DISC1 missense mutation rs821616 (Ser704Cys) single nucleotide polymorphism (SNP) and four other SNPs (rs1772702, rs1754603, rs821621, rs821624) in the related haplotype block and schizophrenia in the Japanese population. We could not find a significant association of selected SNPs with schizophrenia after correction for multiple testing. We performed a meta-analysis of the Ser704Cys variant in schizophrenia using data from the present study and five previous Japanese population studies, and found no association with schizophrenia. We also examined DISC1 immunoreactivity in postmortem prefrontal cortex specimens of schizophrenia patients compared to control samples. The immunoreactivity revealed a significant decrease of DISC1 protein expression in the schizophrenia samples after ruling out potential confounding factors. However, the Ser704Cys variant did not show effects on DISC1 immunoreactivity. These results provide evidence that this functional genetic variation of DISC1 do not underlie the pathophysiology of schizophrenia in the Japanese population.