Guided motor training induces dendritic spine plastic changes in adult rat cerebellar purkinje cells

Schizophrenia is a complex disorder with a high heritability. Relatives with schizophrenia have an increased risk not only for schizophrenia but also for schizophrenia spectrum disorders, such as schizotypal personality disorder. A single nucleotide polymorphism (SNP), rs1344706, in the Zinc Finger Protein 804A (ZNF804A) gene, has been implicated in susceptibility to schizophrenia by several genome-wide association studies, follow-up association studies and meta-analyses. This SNP has been shown to affect neuronal connectivities and cognitive abilities. We investigated an association between the ZNF804A genotype of rs1344706 and schizotypal personality traits using the Schizotypal Personality Questionnaire (SPQ) in 176 healthy subjects. We also looked for specific associations among ZNF804A polymorphisms and the three factors of schizotypy-cognitive/perceptual, interpersonal and disorganization-assessed by the SPQ. The total score for the SPQ in carriers of the risk T allele was significantly higher than that in individuals with the G/G genotype (p=0.042). For the three factors derived from the SPQ, carriers with the risk T allele showed a higher disorganization factor (p=0.011), but there were no differences in the cognitive/perceptual or interpersonal factors between genotype groups (p>0.30). These results suggest that the genetic variation in ZNF804A might increase susceptibility not only for schizophrenia but also for schizotypal personality traits in healthy subjects.     

Genome-wide supported psychosis risk variant in ZNF804A gene and impact on cortico-limbic WM integrity in schizophrenia

Genome-wide association, case association genetic and meta-analytic studies have highlighted ZNF804A as a robust genome-wide supported susceptibility gene for schizophrenia (SCZ). In view of the possible involvement of ZNF804A gene in early neurodevelopment and cellular processes including oligodendrocyte proliferation and differentiation, we examined the effect of ZNF804A on brain WM (WM) integrity in patients with SCZ. Based on extant data in healthy controls (HC), we hypothesized that ZNF804A risk variant rs1344706 is associated with lower fractional anisotropy (FA) in brain regions within cortico-limbic circuits, namely frontal, parietal, medial temporal lobes, and cingulate gyri in SCZ. A total of 200 Chinese participants (125 patients with DSM-IV diagnosis of SCZ and 75 controls) were genotyped using blood samples, a subset of 153 participants (89 patients with DSM-IV diagnosis of SCZ and 64 controls) underwent structural magnetic resonance imaging and diffusion tensor imaging (DTI). There are significant effects of diagnosis (left cingulate gyrus: Adjusted F(1,149) =?9.36, P?=?0.003) and diagnosis-genotype interactions (left parietal lobe: Adjusted F(1,147) =?7.39, P?=?0.007; right parietal lobe: Adjusted F(1,147) =?6.95, P?=?0.009; right medial temporal lobe: Adjusted F(1,147) =?8.79, P?=?0.004; left cingulate gyrus: Adjusted F(1,147) =?8.02, P?=?0.005). Specifically, we found that patients with SCZ who are risk T homozygotes have lower FA in bilateral parietal lobes, and left cingulate gyrus compared with G carriers. Compared with risk T homozygotes in HC, patients with SCZ who are risk T homozygotes have decreased FA in bilateral parietal lobes, and left cingulate gyrus as well as right medial temporal lobe. Our findings suggest that ZNF804A risk variant influence WM integrity involving cortico-limbic brain regions in SCZ and highlight the importance of investigating the impact of genome-wide supported risk factors on intermediate phenotypes with potential to shed light on the neurobiology of SCZ.     

首发精神分裂症患者中ZNF804Ars1344706多态性与非典型抗精神病药疗效间的关联分析

目的: 研究首发精神分裂症患者中 ZNF804A 基因rs1344706多态性与非典型抗精神病药疗效间潜在的关系。方法: 71例首发精神分裂症住院患者作为研究对象,随机接受奥氮平、齐拉西酮或阿立哌唑单药治疗4周,所有受试者在基线和治疗结束时均接受1次阳性和阴性症状量表(PANSS)的评定,利用直接测序法确定每位受试者的 ZNF804A rs1344706位点的基因型。结果: 3组不同基因型的首发精神分裂症患者其治疗前后PANSS总分及阳性因子分的变化存在着显著差异(PANSS总分:F=4.608, df=2, P＜0.05;PANSS阳性因子分:F=4.183, df=2, P＜0.05); T携带者的PANSS总分和阳性因子分的改善显著小于G纯合子患者(PANSS总分:F=8.724, df=1, P＜0.01;PANSS阳性因子分:F=9.392, df=1, P＜0.01)。结论: 在首发精神分裂症患者中, ZNF804A rs1344706基因型与非典型抗精神病药物的疗效呈显著相关。     

Evaluation of risk loci for schizophrenia derived from genome‐wide association studies in a German population

In the genome‐wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053–1055] a UK‐sample of 479 cases with DSM‐IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK‐sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP‐marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P = 1.61 × 10^?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome‐wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93–1.26 95% CI) for the schizophrenia sample and 1.04 (0.90–1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta‐analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. © 2011 Wiley‐Liss, Inc.     

Associations between PXK and TYK2 polymorphisms and systemic lupus erythematosus: a meta-analysis

Objective

The aim of this study was to determine whether phox homology domain containing serine/threonine kinase (PXK) and tyrosine kinase 2 (TYK2) confer susceptibility to systemic lupus erythematosus (SLE).

Materials and methods

The authors conducted meta-analyses on associations between SLE susceptibility and the rs6445975 polymorphism of PXK and the rs2304256, rs12720270, rs280519, and rs1272036 polymorphisms of TYK2.

Results

A total of 13 separate comparisons studies were included in this meta-analysis. Meta-analysis identified an association between SLE and the 2 allele of the rs6445975 polymorphism in the overall population [odds ratio (OR)?=?1.151, 95?% confidence interval (CI)?=?1.086–1.291, P?=?1.8E?06]. Stratification by ethnicity identified a significant association between this polymorphism and SLE in Europeans (OR?=?1.198, 95?% CI?=?1.118–1.285, P?=?3.4E?07), but not in Asians. Meta-analysis identified a significant negative association between SLE and the 2 allele of the rs2304256 polymorphism in the overall population (OR?=?0.808, 95?% CI?=?0.659–0.990, P?=?0.040), and a significant negative association was found in Europeans, but not in Asians.

Conclusions

This meta-analysis shows that the rs6445975 polymorphism of PXK and the rs2304256 polymorphism of TYK2 are associated with the development of SLE in Europeans.     

Associations between interleukin-23R and interleukin-12B polymorphisms and psoriasis susceptibility: a meta-analysis

Objective: The aim of this study was to determine whether interleukin (IL)-23?R and IL-12B polymorphisms confer susceptibility to psoriasis.

Methods: The authors conducted a meta-analysis on associations between the IL-23?R and IL-12B polymorphisms and psoriasis susceptibility.

Results: A total of 14 comparison studies were included in this meta-analysis. The meta-analysis identified a significant association between psoriasis and 2 alleles of the rs11209026 and rs7530511 polymorphisms in Europeans (odds ratio [OR]?=?0.624, 95% confidence interval [CI]?=?0.565–0.697, p?<?1.0?×?10^?8; OR?=?0.804, 95% CI?=?0.743–0.869, p?=?3.0?×?10^?7, respectively). Meta-analysis of IL-12B showed a significant association between the 2 alleles of the rs6887695 and rs3212227 polymorphisms and the risk of developing psoriasis (OR?=?0.710, 95% CI?=?0.673–0.749, p?<?1.0?×?10^?8; OR?=?0.684, 95% CI?=?0.639–0.731, p?<?1.0?×?10^?8, respectively). Stratification by ethnicity identified an association between the rs6887695 and rs3212227 polymorphisms and psoriasis in Europeans.

Conclusions: This meta-analysis showed that the IL-23?R (rs11209026 and rs7530511) polymorphisms are associated with psoriasis risk in Europeans and that the IL-12B (rs6887695 and rs3212227) polymorphisms are associated with susceptibility to psoriasis in Europeans.     

Polymorphism in semaphorin 5A (Sema5A) gene is not a marker of Parkinson's disease risk

A SNP rs7702187 within the semaphorin 5A gene (Sema5A) has been recently associated with sporadic Parkinson's disease (PD) risk in American Caucasians. In the present study frequencies of rs7702187 was determined in two independent populations involving 427 sporadic PD patients (235 Polish Caucasians and 192 Asians from Singapore) and 412 healthy controls (220 Caucasians and 192 Asians), with the use of PCR-RFLP assay. The frequencies of the minor allele were found to be very similar in PD patients and healthy controls in both populations studied: 0.147 versus 0.143 in Caucasian, and 0.224 versus 0.221 in Asian, respectively. Our research does not confirm the previous observation, as no relationship was found between polymorphism within Sema5A gene and the risk of PD. It can be concluded that rs7702187 SNP in Sema5a gene is not a marker of PD risk in the studied populations.     

The Fc receptor-like 3 gene polymorphisms and susceptibility to autoimmune diseases: An updated meta-analysis

Abstract

Previous studies have identified several single nucleotide polymorphisms (SNPs) of Fc receptor-like 3 (FCRL3), an excellent susceptibility gene, as predisposing factors for human autoimmune diseases (ADs). However, the results remain inconclusive. To assess the effect of four selected SNPs (rs7528684, rs11264799, rs945635 and rs3761959), we conducted a meta-analysis with 34 case-control studies. Summary odd ratios (ORs) and 95% confidence intervals (95% CIs) for the polymorphisms in FCRL3 and ADs risk were evaluated. Furthermore, this meta-analysis was performed by using allele comparisons, as well as stratified analyses by ethnicity and disease phenotypes under different genetic models. Our data showed that the TC, TT?+?TC genotypes of rs7528684 contributed to a lower risk of ADs, compared with the CC carriers (OR?=?0.91, 95% CI?=?0.85–0.97; OR?=?0.91, 95% CI?=?0.85–0.98). In comparison with rs7528684 TC genotype, the TT?+?CC carriers were significantly associated with higher ADs risk (OR?=?1.03, 95% CI?=?1.00–1.07). In terms of stratified analyses by ethnicity and disease phenotypes, there were significant associations of rs7528684 polymorphism both with ADs in Asians and Europeans, and with rheumatoid arthritis, Graves’ disease, type-1 diabetes, and other ADs under different genetic models. Moreover, significant associations were also found to be correlated with ADs risk for the SNP rs11264799 in mixed subgroup, for rs945635 in Europeans, North Americans and mixed group, and for rs3761959 in North Americans. These findings indicate that the polymorphisms in FCRL3 may play a role in the pathogenesis of ADs.     

Recapitulation of genome-wide association studies on pulse pressure and mean arterial pressure in the Korean population

Increased pulse pressure (PP) and decreased mean arterial pressure (MAP) are strong prognostic predictors of adverse cardiovascular events. Recently, the International Consortium for Blood Pressure Genome-Wide Association Studies (ICBP-GWAS) reported eight loci that influenced PP and MAP. The ICBP-GWAS examined 51 cohorts--comprising 122?671 individuals of European ancestry--and identified eight SNPs: five that governed PP and three that controlled MAP. Six of these loci were novel. To replicate these newly identified loci and examine genetic architecture of PP and MAP between European and Asian populations, we conducted a meta-analysis of the eight SNPs combining data from ICBP and general population-based Korean cohorts. Two SNPs (rs13002573 (FIGN) and rs871606 (CHIC2)) for PP and two SNPs (rs1446468 (FIGN) and rs319690 (MAP4)) for MAP were replicated in Koreans. Although our GWAS only found moderate association, we believe that the findings promote us to propose that a similar genetic architecture governs PP and MAP in Asians and Europeans. However, further studies will be needed to confirm the possibility using other Asian population.     

UGT1A1 is a major locus influencing bilirubin levels in African Americans

Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10⁻⁸. The lowest P-value was 1.7 × 10⁻²² for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10⁻¹¹; this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r²≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations.     

Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans and confirmed by meta-analysis of published linkage data. Systematic fine mapping using extended Icelandic pedigrees identified an associated haplotype in the gene neuregulin 1 (NRG1), also known as heuregulin, glial growth factor, NDF43 and ARIA. A 290 kb core at risk haplotype at the 5' end of the gene (HAP(ICE)), defined by five SNPs and two microsatellite polymorphisms was found to be associated with schizophrenia in the Icelandic and Scottish populations. A number of subsequent independent studies have attempted to replicate the association, and while some have been successful, the associated haplotype is not always HAP(ICE). Furthermore, no obviously functional or pathogenic variants have been identified, and the relationship between the gene and schizophrenia has remained inconclusive. To reconcile these conflicting findings and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 13 published population-based and family-based association studies up to November 2005. We analysed data from the SNP markers SNP8NRG241930, SNP8NRG243177, SNP8NRG221132 and SNP8NRG221533, and the microsatellite markers 478B14-848, 420M9-1395. Across these studies, strong positive association was found for all six polymorphisms. The haplotype analysis also showed significant association in the pooled international populations (OR=1.22, 95% CI 1.15-1.3, P=8 x 10(-10)). In Asian populations, the risk haplotype was focused around the two microsatellite markers, 478B14-848, 420M9-1395 (haplotype block B), and in Caucasian populations with the remaining four SNP markers (haplotype block A). This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations.     

Linkage disequilibrium structure of the 5q31-33 region in a Thai population

A number of loci related to the immune response are located on human chromosomal region 5q31-33, and polymorphisms in this region have been reported to be associated with autoimmune and infectious diseases. In Southeast Asian populations, no systematic survey with dense SNP markers has been performed for the 5q31-33 region. In this study, the LD and haplotype structures for a 472-kb region on 5q31 were investigated in a Thai population to provide useful information for association studies. In addition, the LD structure in Thais was compared with that of the CHB and JPT HapMap populations (CHB + JPT) to evaluate the transferability of tagging SNPs from CHB + JPT for Thais. We show that the minor allele frequency, pattern of LD block, and genetic structure in the 5q31-33 region were highly concordant between Thais and CHB + JPT. A high transferability of tagging SNPs from CHB + JPT for Thais was observed. Our results suggest that tagging SNPs from CHB + JPT (Northeast Asians) can efficiently capture common variants in Southeast Asians, and that the HapMap data are useful for association studies in Southeast Asian populations.     

GSK3β reduces risk of sporadic Parkinson's disease in ethnic Chinese

Genetic variability of glycogen synthase kinase-3β (GSK3β) may be linked to Parkinson's disease (PD). Its role in ethnic Chinese population is still unclear. We examined the association between GSK3β variation and PD in a Han Chinese population from mainland China. Using a case-control methodology, we genotyped the single nucleotide polymorphism (SNP) in GSK3β (rs334558) to investigate the association with risk of PD. A total of 1,280 ethnic Han Chinese study subjects comprising 761 sporadic PD patients and 519 controls were recruited. The T allele of a promoter SNP rs334558 was found to reduce the risk of PD (OR?=?0.82, 95% CI: 0.696-0.960, P?=?0.014). Patients with CT?+?TT genotypes have a reduced risk of PD compared to those with CC genotype (OR?=?0.61, 95% CI: 0.477-0.776, P?=?6.09E-5). In addition, we demonstrated that CT?+?TT subjects cannot be distinguished from CC subjects based on their clinical features. Our data suggest that rs334558 variant in GSK3β reduces the risk of PD in a Han Chinese population from mainland China. Further studies of large series of subjects are necessary to fully elucidate the true role of GSK3β in PD. ? 2012 Wiley Periodicals, Inc.     

A Single Nucleotide Polymorphism of IL-21 Gene is Associated with Systemic Lupus Erythematosus in a Chinese Population

The aim of this study was to examine the association of single-nucleotide polymorphisms (SNPs) in IL-21 gene with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. A total of 605 independent SLE patients and 666 unrelated healthy controls were recruited for the case?Ccontrol association study. Two SNPs (rs2221903 and rs907715) within the IL-21 gene intronic region were genotyped by TaqMan SNP allelic discrimination methods. The allele T frequency of SNP rs2221903 in patients and healthy controls was 89.4?% and 86.8?%, respectively [T versus C, odds ratio (OR)?=?1.287, 95?% confidence interval (CI)?=?1.010?C1.640]. No significant differences in genotype frequencies were shown between SLE patients and healthy controls (P value?=?0.705, 0.406, respectively). However, the effect of recessive model (TT versus CC?+?CT, OR?=?1.368, 95?% CI?=?1.050?C1.781) was observed. Distributions of allele and genotype frequencies of the SNP rs907715 showed no significant differences between SLE patients and controls. Analysis of the haplotypes revealed that CC haplotype was significantly associated with SLE (OR?=?0.734, 95?% CI?=?0.573?C0.941). In conclusion, our findings suggest that a SNP (rs2221903) and CC haplotype (rs2221903 and rs907715) of the IL-21 gene is associated with SLE in the Chinese population. However, further studies are needed to determine the functional consequences of this polymorphism with SLE susceptibility.     

Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults

Recent evidence indicates that genetic variation in fatty acid desaturases 1 and 2 (FADS1 and FADS2) is associated with changes in plasma fatty acid profiles; however, the association with altered desaturase activity has not been examined in different ethnic populations. The present study examined whether genetic variation in the FADS gene cluster regulates desaturase activity in two populations of young Canadian adults (Caucasian and Asian) and whether altered desaturase activity was reflected in both n-3 and n-6 fatty acid profiles. FADS1 and FADS2 were genotyped in a random subset of participants (Caucasian, n=78; Asian, n=69) from the Toronto Nutrigenomics and Health study using MALDI-TOF mass spectrometry, and plasma fatty acids were measured by gas chromatography. Desaturase activities were estimated using the following fatty acid ratios: γ-linoleic acid to linoleic acid (GLA:LA), arachidonic acid to linoleic acid (AA:LA), arachidonic acid to dihomo-γ-linoleic acid (AA:DGLA), and eicosapentaneoic acid to α-linolenic acid (EPA:ALA). Nineteen single nucleotide polymorphisms (SNPs) were examined, and several SNPs (9 in Caucasians and 8 in Asians) were associated with various desaturase activities. The most significant association detected was between the FADS1 rs174547 SNP and AA:LA in both Caucasians (p=4.0 × 10(-8)) and Asians (p=5.0 × 10(-5)). Although the minor allele for this SNP differed between Caucasians (T) and Asians (C), carriers of the C allele had a lower desaturase activity than carriers of the T allele in both groups. To determine whether rs174547 was a dominant SNP in the FADS gene cluster, we constructed an additional model which included this SNP as a covariate. Only one SNP (rs498793 in FADS2) remained associated with the EPA:ALA ratio (p=1.1 × 10(-5)) in Asians. This study shows that genetic variation in the FADS gene cluster (in particular rs174547) can alter desaturase activity in subjects of Caucasians and Asian descent.     

Genetic variants associated with breast size also influence breast cancer risk

ABSTRACT: BACKGROUND: While some factors of breast morphology, such as density, are directly implicated in breast cancer, the relationship between breast size and cancer is less clear. Breast size is moderately heritable, yet the genetic variants leading to differences in breast size have not been identified. METHODS: To investigate the genetic factors underlying breast size, we conducted a genome-wide association study (GWAS) of self-reported bra cup size, controlling for age, genetic ancestry, breast surgeries, pregnancy history and bra band size, in a cohort of 16,175 women of European ancestry. RESULTS: We identified seven single-nucleotide polymorphisms (SNPs) significantly associated with breast size (p < 5 . 10-8): rs7816345 near ZNF703, rs4849887 and (independently) rs17625845 flanking INHBB, rs12173570 near ESR1, rs7089814 in ZNF365, rs12371778 near PTHLH, and rs62314947 near AREG. Two of these seven SNPs are in linkage disequilibrium (LD) with SNPs associated with breast cancer (those near 1 ESR1 and PTHLH), and a third (ZNF365) is near, but not in LD with, a breast cancer SNP. The other three loci (ZNF703, INHBB, and AREG) have strong links to breast cancer, estrogen regulation, and breast development. CONCLUSIONS: These results provide insight into the genetic factors underlying normal breast development and show that some of these factors are shared with breast cancer. While these results do not directly support any possible epidemiological relationships between breast size and cancer, this study may contribute to a better understanding of the subtle interactions between breast morphology and breast cancer risk.     

A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5' UTR of GDF5 with osteoarthritis susceptibility

We have performed a meta-analysis combining data for more than11 000 individuals. It provides compelling evidence for a positiveassociation between a functional single-nucleotide polymorphism(SNP) in the 5'-UTR of GDF5 (+104T/C; rs143383) and osteoarthritis(OA) in European and Asian populations. This SNP has recentlybeen reported to be associated with OA in Japanese and Han Chinesepopulations. Attempts to replicate this association in Europeansamples have been inconclusive, as no association was foundin the case–control cohorts from the UK, Spain and Greecewhen studied individually. However, the pooled data of UK andSpain found an association of the T-allele with an odds ratio(OR) of 1.10. Although the European studies had adequate powerto replicate the original findings from the Japanese cohort(OR = 1.79), these results suggest that the role of the GDF5polymorphism may not be as strong in Europeans. To clarify whetherthe European studies were hampered by insufficient power, wecombined new data from the UK and the Netherlands with the threepublished studies of Europe and Asia. The results provide strongevidence of a positive association of the GDF5 SNP with kneeOA for Europeans as well as for Asians. The combined associationfor both ethnic groups is highly significant for the allelefrequency model (P = 0.0004, OR = 1.21) and the dominant model(P < 0.0001, OR = 1.48). These findings represent the firsthighly significant evidence for a risk factor for the developmentof OA which affects two highly diverse ethnic groups.