排序方式: 共有74条查询结果,搜索用时 15 毫秒
41.
Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile 总被引:1,自引:0,他引:1
Kilpeläinen TO Zillikens MC Stančákova A Finucane FM Ried JS Langenberg C Zhang W Beckmann JS Luan J Vandenput L Styrkarsdottir U Zhou Y Smith AV Zhao JH Amin N Vedantam S Shin SY Haritunians T Fu M Feitosa MF Kumari M Halldorsson BV Tikkanen E Mangino M Hayward C Song C Arnold AM Aulchenko YS Oostra BA Campbell H Cupples LA Davis KE Döring A Eiriksdottir G Estrada K Fernández-Real JM Garcia M Gieger C Glazer NL Guiducci C Hofman A Humphries SE Isomaa B Jacobs LC Jula A Karasik D Karlsson MK 《Nature genetics》2011,43(8):753-760
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance. 相似文献
42.
Weedon MN Lango H Lindgren CM Wallace C Evans DM Mangino M Freathy RM Perry JR Stevens S Hall AS Samani NJ Shields B Prokopenko I Farrall M Dominiczak A;Diabetes Genetics Initiative;Wellcome Trust Case Control Consortium Johnson T Bergmann S Beckmann JS Vollenweider P Waterworth DM Mooser V Palmer CN Morris AD Ouwehand WH;Cambridge GEM Consortium Zhao JH Li S Loos RJ Barroso I Deloukas P Sandhu MS Wheeler E Soranzo N Inouye M Wareham NJ Caulfield M Munroe PB Hattersley AT McCarthy MI Frayling TM 《Nature genetics》2008,40(5):575-583
Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait. 相似文献
43.
Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
Elks CE Perry JR Sulem P Chasman DI Franceschini N He C Lunetta KL Visser JA Byrne EM Cousminer DL Gudbjartsson DF Esko T Feenstra B Hottenga JJ Koller DL Kutalik Z Lin P Mangino M Marongiu M McArdle PF Smith AV Stolk L van Wingerden SH Zhao JH Albrecht E Corre T Ingelsson E Hayward C Magnusson PK Smith EN Ulivi S Warrington NM Zgaga L Alavere H Amin N Aspelund T Bandinelli S Barroso I Berenson GS Bergmann S Blackburn H Boerwinkle E Buring JE Busonero F Campbell H Chanock SJ Chen W Cornelis MC 《Nature genetics》2010,42(12):1077-1085
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10???) and 9q31.2 (P = 2.2 × 10?33), we identified 30 new menarche loci (all P < 5 × 10??) and found suggestive evidence for a further 10 loci (P < 1.9 × 10??). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing. 相似文献
44.
The increase in oil price volatility in recent years has raised the importance of forecasting it accurately for valuing and hedging investments. The paper models and forecasts the crude oil exchange‐traded funds (ETF) volatility index, which has been used in the last years as an important alternative measure to track and analyze the volatility of future oil prices. Analysis of the oil volatility index suggests that it presents features similar to those of the daily market volatility index, such as long memory, which is modeled using well‐known heterogeneous autoregressive (HAR) specifications and new extensions that are based on net and scaled measures of oil price changes. The aim is to improve the forecasting performance of the traditional HAR models by including predictors that capture the impact of oil price changes on the economy. The performance of the new proposals and benchmarks is evaluated with the model confidence set (MCS) and the Generalized‐AutoContouR (G‐ACR) tests in terms of point forecasts and density forecasting, respectively. We find that including the leverage in the conditional mean or variance of the basic HAR model increases its predictive ability. Furthermore, when considering density forecasting, the best models are a conditional heteroskedastic HAR model that includes a scaled measure of oil price changes, and a HAR model with errors following an exponential generalized autoregressive conditional heteroskedasticity specification. In both cases, we consider a flexible distribution for the errors of the conditional heteroskedastic process. 相似文献
45.
In order for any biological system to function effectively, it is essential to avoid the inherent tendency of proteins to aggregate and form potentially harmful deposits. In each of the various pathological conditions associated with protein deposition, such as Alzheimer's and Parkinson's diseases, a specific peptide or protein that is normally soluble is deposited as insoluble aggregates generally referred to as amyloid. It is clear that the aggregation process is generally initiated from partially or completely unfolded forms of the peptides and proteins associated with each disease. Here we show that the intrinsic effects of specific mutations on the rates of aggregation of unfolded polypeptide chains can be correlated to a remarkable extent with changes in simple physicochemical properties such as hydrophobicity, secondary structure propensity and charge. This approach allows the pathogenic effects of mutations associated with known familial forms of protein deposition diseases to be rationalized, and more generally enables prediction of the effects of mutations on the aggregation propensity of any polypeptide chain. 相似文献
46.
Frezza C Zheng L Folger O Rajagopalan KN MacKenzie ED Jerby L Micaroni M Chaneton B Adam J Hedley A Kalna G Tomlinson IP Pollard PJ Watson DG Deberardinis RJ Shlomi T Ruppin E Gottlieb E 《Nature》2011,477(7363):225-228
Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients. 相似文献
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48.
Massimo Ferrari 《Studies in history and philosophy of science》2012,43(1):18-26
This paper provides a critical evaluation of Friedman’s arguments in favour of a relativized a priori resting on Cassirer’s Neo-Kantianism, Reichenbach’s and Carnap’s constitutive a priori, and finally Kuhn’s account of scientific paradigms change. The main objection concerns Cassirer’s own view of dynamic and historical moveable a priori categories, which Friedman seems to underestimate and recasts in a merely regulative function. However, Cassirer conception of a “liberalized” a priori can shed new light on the process of scientific change and his transcendental method may be considered as a still stimulating alternative to Kuhn’s and post-Kuhnian relativism in the philosophy of science. 相似文献
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50.
Climate policies making are strongly impacted by the approach of damage evaluation.China is leading carbon dioxide(CO_2) emissions in the world, and has agreed with Paris agreement to reduce CO_2 emissions. China is also expected to be negatively impacted by climate change. One of main concerns is how to assess and monetize the climate damage from country-specific level. This paper builds a model comprising two approaches of damage evaluation and assesses China's mitigation and adaptation responses by 2100 for both of no policy and Paris agreement policy. It has the following findings: First, the emissions pathway and nonfossil fuel consumption share of total energy consumption differs slightly between the two approaches of damage evaluation. Second, with the Burkes approach,the climate damage avoided by adaptation is increasingly higher than that by mitigation when investment in adaptation starts to be massively injected with faster increasing trend by 2045. Third, climate expenses should be invested more to address higher level of the climate damage evaluated by the Burkes approach than by the Mannes approach. Fourth, the main findings in this paper are robust in terms of uncertainties in the parameters of damage function. 相似文献