Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.     

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.     

Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis

We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.     

JWA参与调控细胞分化的结构和功能研究

为阐明新基因JWA的结构特征、表达调节规律和生物学功能,通过基因重组和测序,确定了大鼠JWA同源基因和人JWA基因621bp的启动子序列;用RT-PCR法,分析了培养细胞株和原代白血病细胞经药物处理后JWAmRNA的表达情况,发现TPA处理后JWAmRNA水平在肿瘤细胞株与非肿瘤细胞株中呈反向变化;用维甲酸治疗前的M3型白血病人骨髓白细胞,其JWA基因对多种诱导分化剂处理不敏感;而用维甲酸治疗10d后再用诱导分化剂处理,则JWA基因的转录水平均被下调,提示M3型白血病细胞在ATRA作用下的分化可能是启动JWA信号转导通路的前提,而JWA基因的表达下调是否为白血病细胞进一步分化及4HPR,As     

JWA参与调控细胞分化的结构和功能

为阐明新基因JWA的结构特征、表达调节规律和生物学功能,通过基因重组和测序,确定了大鼠JWA同源基因和人JWA基因621bp的启动子序列;用RT－PCR法,分析了培养细胞株和原代白血病细胞经药物处理后JWA mRNA的表达情况,发现TPA处理后JWAmRNA水平在肿瘤细胞株与非肿瘤细胞株中呈反向变化：用维甲酸治疗前的M3型白血病人骨髓白细胞,其JWA基因对多种诱导分化剂处理不敏感;而用维甲酸治疗10d后再用诱导分化剂处理,则JWA基因的转录水平均被下调,提示M3型白血病细胞在ATRA作用下的分化可能是启动JWA信号转导通路的前提。而JWA基因的表达下调是否为白血病细胞进一步分化及4HPR,As2O3和TPA等诱导细胞凋亡所必需,值得进一步探讨。JWA基因在不同种属中保持较为稳定的序列特征,说明该基因在生物进化中可能较保守并可能具有相近的生物学功能。     

THEMIS星座对2008年2月26日磁层亚暴的观测--磁尾重联触发的亚暴分析研究

本文利用THEMIS卫星结合地面极光和地磁的观测,研究了2008年2月26日04：05和04：55UT的两次亚暴事件.Angelopoulos已经对发生在04：55UT的第二个亚暴事件做了分析.本文对两次亚暴的相关活动进行了详细研究,特别对第一次做了深入讨论,并着重分析了磁重联与亚暴活动的关系.在两次亚暴的初始阶段,第一次极光增亮发生在中磁尾磁重联后2～3min,但是持续时间较短,极向膨胀缓慢,与伪暴的特征相似,标志了亚暴的初突发（initial onset）.两次亚暴都存在第二次极光增亮和极光的极向膨胀,且时间与近地磁尾观测的地向流和磁场偶极化同时发生,并与亚暴膨胀相的其他活动的发生同步,标志了亚暴的主突发（major onset）.在两次亚暴的增长相期间,极盖区开放磁通量持续增加;在亚暴膨胀相和恢复相中,极盖区磁通量迅速减少.表明两次亚暴膨胀相的演化分别与两次尾瓣开放磁力线重联过程相联系的.从亚暴活动的参数分析,这两次亚暴都属于小亚暴范围;从重联率分析,两次磁重联都属于弱重联.本文的观测结果表明,中磁尾磁尾重联首先触发伪暴;高速流将磁通量和能量传输到近地磁尾;高速流减速最终导致亚暴...更多电流楔（substorm current wedge,简称SCW）的形成和电流中断,产生近地偶极化和极光膨胀,引起亚暴膨胀相突发.本文的观测结果是对近地中性线模型（near earth neutral line,简称NENL）和重联-电流中断协同模型（synthesis scenario of MR and CD,简称RCS）模型及亚暴膨胀相两步突发观点的有力支持.     

Genome-wide association studies of 14 agronomic traits in rice landraces

Uncovering the genetic basis of agronomic traits in crop landraces that have adapted to various agro-climatic conditions is important to world food security. Here we have identified ～ 3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data-imputation method. We performed genome-wide association studies (GWAS) for 14 agronomic traits in the population of Oryza sativa indica subspecies. The loci identified through GWAS explained ～ 36% of the phenotypic variance, on average. The peak signals at six loci were tied closely to previously identified genes. This study provides a fundamental resource for rice genetics research and breeding, and demonstrates that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice.     

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.     

Nesprin interchain associations control nuclear size

Nesprins-1/-2/-3/-4 are nuclear envelope proteins, which connect nuclei to the cytoskeleton. The largest nesprin-1/-2 isoforms (termed giant) tether F-actin through their N-terminal actin binding domain (ABD). Nesprin-3, however, lacks an ABD and associates instead to plectin, which binds intermediate filaments. Nesprins are integrated into the outer nuclear membrane via their C-terminal KASH-domain. Here, we show that nesprin-1/-2 ABDs physically and functionally interact with nesprin-3. Thus, both ends of nesprin-1/-2 giant are integrated at the nuclear surface: via the C-terminal KASH-domain and the N-terminal ABD-nesprin-3 association. Interestingly, nesprin-2 ABD or KASH-domain overexpression leads to increased nuclear areas. Conversely, nesprin-2 mini (contains the ABD and KASH-domain but lacks the massive nesprin-2 giant rod segment) expression yields smaller nuclei. Nuclear shrinkage is further enhanced upon nesprin-3 co-expression or microfilament depolymerization. Our findings suggest that multivariate intermolecular nesprin interactions with the cytoskeleton form a lattice-like filamentous network covering the outer nuclear membrane, which determines nuclear size.     

The impact of cyclin-dependent kinase 5 depletion on poly(ADP-ribose) polymerase activity and responses to radiation

Cyclin-dependent kinase 5 (Cdk5) has been identified as a determinant of sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the consequences of its depletion on cell survival, PARP activity, the recruitment of base excision repair (BER) proteins to DNA damage sites, and overall DNA single-strand break (SSB) repair were investigated using isogenic HeLa stably depleted (KD) and Control cell lines. Synthetic lethality achieved by disrupting PARP activity in Cdk5-deficient cells was confirmed, and the Cdk5^KD cells were also found to be sensitive to the killing effects of ionizing radiation (IR) but not methyl methanesulfonate or neocarzinostatin. The recruitment profiles of GFP-PARP-1 and XRCC1-YFP to sites of micro-irradiated Cdk5^KD cells were slower and reached lower maximum values, while the profile of GFP-PCNA recruitment was faster and attained higher maximum values compared to Control cells. Higher basal, IR, and hydrogen peroxide-induced polymer levels were observed in Cdk5^KD compared to Control cells. Recruitment of GFP-PARP-1 in which serines 782, 785, and 786, potential Cdk5 phosphorylation targets, were mutated to alanines in micro-irradiated Control cells was also reduced. We hypothesize that Cdk5-dependent PARP-1 phosphorylation on one or more of these serines results in an attenuation of its ribosylating activity facilitating persistence at DNA damage sites. Despite these deficiencies, Cdk5^KD cells are able to effectively repair SSBs probably via the long patch BER pathway, suggesting that the enhanced radiation sensitivity of Cdk5^KD cells is due to a role of Cdk5 in other pathways or the altered polymer levels.