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| 2. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 3. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 4. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 5. |
- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 6. |
- Wang, Peng-Fei, et al.
(författare)
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A novel self-refreshable capacitorless DRAM cell and its extended applications
- 2010
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Ingår i: Solid-State Electronics. - : Elsevier BV. - 0038-1101 .- 1879-2405. ; 54:9, s. 985-990
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Tidskriftsartikel (refereegranskat)abstract
- A novel DRAM cell based on floating junction gate (FJG) concept is investigated for its extended applications. Compared to the two-transistor floating gate DRAM cell, the new memory cell investigated in the present work has a much simpler configuration with only one transistor. Besides, its write speed is improved by introducing an integrated gated-diode so that state “1” can be self-refreshable. In this paper, the device configuration, the DRAM application feasibility, the self-refreshing ability, and the non-destructive read are explored. In addition, extended applications of the DRAM cell using the FJG concept will be discussed.
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| 7. |
- Alonso-Blanco, Carlos, et al.
(författare)
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1,135 Genomes Reveal the Global Pattern of Polymorphism in Arabidopsis thaliana
- 2016
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Ingår i: Cell. - : Elsevier. - 0092-8674 .- 1097-4172. ; 166:2, s. 481-491
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Tidskriftsartikel (refereegranskat)abstract
- Arabidopsis thaliana serves as a model organism for the study of fundamental physiological, cellular, and molecular processes. It has also greatly advanced our understanding of intraspecific genome variation. We present a detailed map of variation in 1,135 high-quality re-sequenced natural inbred lines representing the native Eurasian and North African range and recently colonized North America. We identify relict populations that continue to inhabit ancestral habitats, primarily in the Iberian Peninsula. They have mixed with a lineage that has spread to northern latitudes from an unknown glacial refugium and is now found in a much broader spectrum of habitats. Insights into the history of the species and the fine-scale distribution of genetic diversity provide the basis for full exploitation of A. thaliana natural variation through integration of genomes and epigenomes with molecular and non-molecular phenotypes.
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| 8. |
- Fan, Jin, et al.
(författare)
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Development of wideband orthomode transducers for FAST cryogenic receiver system
- 2020
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Ingår i: Research in Astronomy and Astrophysics. - : IOP Publishing. - 1674-4527. ; 20:5
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the design, construction, and performance of the wideband orthomode transducers (OMTs) for the L- (1.2-1.8 GHz), the S- (2-3 GHz) and the P- (0.56-1.12 GHz) band receiver systems of the Five-hundred-meter Aperture Spherical radio Telescope (FAST). These OMTs operate at the cryogenic temperature of 70K to reduce their thermal noise contribution to the receiver chains. The development on the FAST L- and S-band quad-ridged waveguide (QRWG) OMTs is carried out based on the theoretical mode analysis. In view of the miniaturization of FAST cryogenic receiver system at P-band, a novel wideband compact bowtie dipole OMT is designed with an octave bandwidth as well as a length of only quarter wavelength. The proposed L-, S- and P-band OMTs are designed and optimized by using Ansys High Frequency Structure Simulator (HFSS), and then manufactured, tested at room temperature. Measurement of FAST cryogenic receiver system noise is also performed with the L-, S- and P-band OMTs installed. The measured results fully comply with the design specifications.
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| 9. |
- Gan, Wensheng, et al.
(författare)
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Utility-Driven Data Analytics on Uncertain Data
- 2020
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Ingår i: IEEE Systems Journal. - : IEEE. - 1932-8184 .- 1937-9234. ; 14:3, s. 4442-4453
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Tidskriftsartikel (refereegranskat)abstract
- Modern Internet of Things (IoT) applications generate massive amounts of data, much of them in the form of objects/items of readings, events, and log entries. Specifically, most of the objects in these IoT data contain rich embedded information (e.g., frequency and uncertainty) and different levels of importance (e.g., unit risk/utility of items, interestingness, cost, or weight). Many existing approaches in data mining and analytics have limitations, such as only the binary attribute is considered within a transaction, as well as all the objects/items having equal weights or importance. To solve these drawbacks, a novel utility-driven data analytics algorithm named HUPNU is presented in this article. As a general utility-driven uncertain data mining model, HUPNU can extract High-Utility patterns by considering both Positive and Negative unit utilities from Uncertain data. The qualified high-utility patterns can be effectively discovered for intrusion detection, risk prediction, manufacturing management, and decision-making, among others. By using the developed vertical Probability-Utility list with the positive and negative utilities structure, as well as several effective pruning strategies, experiments showed that the developed HUPNU approach with the pruning strategies performed great in mining the qualified patterns efficiently and effectively.
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| 10. |
- Gan, Yong, et al.
(författare)
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Association between alcohol consumption and the risk of stroke in middle-aged and older adults in China
- 2021
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Ingår i: Drug And Alcohol Dependence. - : Elsevier BV. - 0376-8716 .- 1879-0046. ; 229
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This study aimed to investigate the association between alcohol consumption and the prevalence of stroke in Chinese adults aged 40 years and over.Method: We conducted a cross-sectional analysis among 113,573 Chinese adults aged >= 40 years in the China National Stroke Prevention Project (2014-2015) to examine correlations of alcohol consumption with the prevalence of stroke. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), controlling for various confounders, e.g., gender, age, smoking, physical activity and other health conditions.Results: Within the study population, a total of 12,753 stroke survivors were identified. The prevalence of light to moderate and of heavy alcohol consumption was 10.1% and 5.7% respectively. The multivariate logistic regression results show that light to moderate alcohol consumption was associated with reduced risk of stroke of all types [0.91 (95%CI: 0.85-0.97)] and of ischemic stroke [0.90 (0.84-0.97)]. No association was found between alcohol consumption and hemorrhagic stroke. Compared with abstainers, the adjusted ORs of all stroke were 0.83 (0.75-0.92) for those who drank 11-20 years, and no association was found between 1 and 10 years or over 20 years of drinking and risk of stroke.Conclusions: These results indicate that light to moderate alcohol consumption may be protective against all and ischemic stroke, and heavy drinking was not significantly associated with risk of all stroke in China. No association between alcohol consumption and hemorrhagic stroke was found.
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