Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.     

A genome-wide association meta-analysis identifies new childhood obesity loci

Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).     

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10(-31) and P = 1.3 × 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.     

Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia

Interleukin 7 (IL-7) and its receptor, formed by IL-7Rα (encoded by IL7R) and γc, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region and promote de novo formation of intermolecular disulfide bonds between mutant IL-7Rα subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, γc or JAK3. IL7R mutations induce a gene expression profile partially resembling that provoked by IL-7 and are enriched in the T-ALL subgroup comprising TLX3 rearranged and HOXA deregulated cases. Notably, IL7R mutations promote cell transformation and tumor formation. Overall, our findings indicate that IL7R mutational activation is involved in human T-cell leukemogenesis, paving the way for therapeutic targeting of IL-7R-mediated signaling in T-ALL.     

理论力学课程的改革与思考

理论力学是高等师范院校物理教育专业开设的一门重要的专业理论课,也是物理教育专业学生应学习的四门理论物理课程中的第一门,它是后继理论物理课程的基础.     

纳米流式检测技术的研发、应用及前景

针对生命科学、生物医药、纳米科技等领域日益增长的单粒子水平纳米颗粒表征需求,本课题组将瑞利散射和鞘流单分子荧光检测技术结合,成功研发了纳米流式检测技术(nano-flow cytometry,nFCM),实现单个纳米颗粒(7～500 nm)以及细胞外囊泡、病毒、细菌、亚细胞器等天然生物纳米颗粒的粒径及其分布、颗粒浓度和...     

群决策中不同形式属性权重信息的集结与应用

针对决策者给出不同形式偏好信息的群决策问题,基于不同形式模糊偏好信息之间的转换公式,将群决策问题中决策者给出的实数值、区间值、语言短语和直觉模糊值4类常见的偏好信息一致化,然后利用集结算子得到综合的有效权重。最后,给出了算例,结果表明方法简单、有效,易于实现。     

基于小波变换的雷达信号特征提取方法

基于小波变换,提出了一种提取雷达信号特征的方法。通过对雷达信号进行小波分解,设置门限,将小波变换系数转换为二进制,然后将二进制小波系数再转换为十进制,这样就得到了雷达信号的特征。通过目标识别实验,证明本文提出的方法是有效的。     

胶体金对小鼠外周血血清和脾脏淋巴细胞诱导白介素2含量的影响

实验设计了4种直径和3种剂量12个组合的胶体金对小白鼠进行注射处理;采用放射性免疫法,测定了外周血血清和脾脏淋巴细胞诱导白介素2含量,结果表明:不同直径和剂量的CG对机体有不同程度的影响,其中直径15 nm,10 nm的CG的0.3 mL和0.2 mL剂量组可显著提高外周血血清和脾脏淋巴细胞诱导白介素2含量,0.1 mL剂量组虽有提高但不显著;直径5 nm,20 nm各个剂量组效果的波动较大,中、高剂量组对4项指标起促进作用但不显著,低剂量组则没有促进作用。证明了15 nm和10 nm中高剂量的胶体金可显著提高外周血血清和脾脏淋巴细胞诱导白介素2含量。