| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 7. |
- Stolk, Lisette, et al.
(författare)
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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 260-268
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Tidskriftsartikel (refereegranskat)abstract
- To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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| 8. |
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| 9. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 10. |
- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- 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 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). 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.
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| 11. |
- Jakobsdottir, Johanna, et al.
(författare)
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Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
- 2016
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.
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| 12. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 15. |
- Bagni, Tommaso, et al.
(författare)
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Modeling Results of the Quench Behavior of a Nb-Ti Canted-Cosine-Theta Corrector Magnet for LHC
- 2024
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Ingår i: IEEE transactions on applied superconductivity (Print). - : Institute of Electrical and Electronics Engineers (IEEE). - 1051-8223 .- 1558-2515. ; 34:5, s. 1-5
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Tidskriftsartikel (refereegranskat)abstract
- A newly designed superconducting magnet of the Canted-Cosine-Theta (CCT) type was developed as a result of a collaboration between Swedish universities (Uppsala and Linneaus) and Swedish industries. This magnet was designed to function as a replacement of the present LHC orbit corrector magnets, which are approaching their end of life due to the radiation load. As a result, the new CCT magnet was developed to be more radiation tolerant and to constitute a one-to-one replacement to the currently installed version, which is a 1 m long 70 mm double aperture dipole magnet. The final magnet, which is currently under construction, will be tested at FREIA laboratory at Uppsala University and generate a magnetic field of 3.3 T and an integrated field of 2.8 Tm at about 85 A. To examine the magnet quench behavior and to identify a suitable quench protection system, the 3D electro-magnetic and thermal behavior of the coil was modeled using the RAT-Raccoon software. Based on the simulation results, a Metrosil varistor was selected to protect the magnet during the test. In this article, we report the results of the numerical analysis. The magnet model is equipped with a spot heater to initialize the quench and the temperature and voltages are monitored during the avalanche effect. The simulated current decay and the hot-spot temperature are analyzed with a focus on the impact of quench-back on the magnet protection.
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| 16. |
- EMILSSON, V, et al.
(författare)
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FACTOR FOR INVERSION STIMULATION-DEPENDENT GROWTH-RATE REGULATION OF SERINE AND THREONINE TRANSFER-RNA SPECIES
- 1995
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Ingår i: JOURNAL OF BIOLOGICAL CHEMISTRY. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0021-9258. ; 270:28, s. 16610-16614
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We have previously shown that the accumulation of 20 tRNA species in Escherichia coli is individually regulated as a function of cellular growth rate. We have also reported that the growth rate regulation of some but not all tRNA species is dependent on t
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| 17. |
- Islam, M. Shahidul, et al.
(författare)
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Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells
- 2000
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 24:10, s. 1246-1253
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Previous studies have demonstrated that leptin can stimulate proliferation of insulin-secreting tumor cell lines. The objective of this study was to characterize whether leptin could stimulate proliferation of primary beta-cells too. Since adult beta-cells have very limited capacity for replication, we examined the effect of leptin on islets of Langerhans obtained from fetal rats, in a tissue culture system. METHODS: Leptin receptor mRNA and c-fos mRNA were measured by RT-PCR. Proliferation of fetal rat islet cells was measured by a WST-1 colorimetric assay and [3H]-thymidine incorporation assay. RESULTS: Leptin stimulated proliferation of serum-deprived fetal rat islet cells, as indicated by increased formation of formazan dye from a tetrazolium salt WST-1. Leptin stimulated DNA synthesis in islet cells, as indicated by increased [3H]-thymidine incorporation into DNA. The effect of leptin on islet cell proliferation was on average 39-50% of the effect obtained with 10% fetal bovine serum. Leptin increased c-fos mRNA expression by 2.8-fold in isolated fetal islets after 30 min treatment. In fetal pancreatic islets, both the common extracellular portion (OB-R) and the intact long form (OB-Rb) of the leptin receptor were readily detected by reverse transcriptase polymerase chain reaction. CONCLUSION: Functional leptin receptors are expressed in pancreatic islet cells, as early as during the fetal stage of development of these microorgans. Leptin stimulates proliferation of fetal islet cells and might play a role in determining islet cell mass at birth.
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| 18. |
- Johansson, Henrik, 1965-, et al.
(författare)
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Prevalence, progression and impact of chronic cough on employment in Northern Europe
- 2021
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 57:6
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the prevalence of chronic cough and its association with work ability and sick leave in the general population. Data were analysed from the Respiratory Health In Northern Europe (RHINE) III cohort (n=13 500), of which 11 252 participants had also participated in RHINE II 10 years earlier, a multicentre study in Northern Europe. Participants answered a questionnaire on chronic cough, employment factors, smoking and respiratory comorbidities. Nonproductive chronic cough was found in 7% and productive chronic cough in 9% of the participants. Participants with nonproductive cough were more often female and participants with productive cough were more often smokers and had a higher body mass index (BMI) than those without cough. Participants with chronic cough more often reported >7 days of sick leave in the preceding year than those without cough (“nonproductive cough” 21% and “productive cough” 24%; p<0.001 for comparisons with “no cough” 13%). This pattern was consistent after adjusting for age, sex, BMI, education level, smoking status and comorbidities. Participants with chronic cough at baseline reported lower work ability and more often had >7 days of sick leave at follow-up than those without cough. These associations remained significant after adjusting for cough at follow-up and other confounding factors. Chronic cough was found in around one in six participants and was associated with more sick leave. Chronic cough 10 years earlier was associated with lower work ability and sick leave at follow-up. These associations were not explained by studied comorbidities. This indication of negative effects on employment from chronic cough needs to be recognised. © 2021 European Respiratory Society. All rights reserved.
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| 19. |
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| 20. |
- Kepp, KP, et al.
(författare)
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Estimates of excess mortality for the five Nordic countries during the COVID-19 pandemic 2020-2021
- 2022
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Ingår i: International journal of epidemiology. - : Oxford University Press (OUP). - 1464-3685 .- 0300-5771. ; 51:6, s. 1722-1732
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundExcess mortality during the COVID-19 pandemic is of major scientific and political interest.MethodsWe critically reviewed different estimates of all-cause excess mortality for the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), which have been much studied during the COVID-19 pandemic, using the latest register data to discuss uncertainties and implications.ResultsWe show using back-calculation of expected deaths from Nordic all-cause deaths that the Institute for Health Metrics and Evaluation model is a clear outlier in the compared estimates and likely substantially overestimates excess mortality of Finland and Denmark, and probably Sweden. Our review suggests a range of total Nordic excess deaths of perhaps 15 000–20 000, but results are sensitive to assumptions in the models as shown.ConclusionsWe document substantial heterogeneity and uncertainty in estimates of excess mortality. All estimates should be taken with caution in their interpretation as they miss detailed account of demographics, such as changes in the age group populations over the study period.
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| 21. |
- Ludvigsson, Jonas F., 1969-, et al.
(författare)
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Increased risk of herpes zoster in patients with coeliac disease - nationwide cohort study
- 2018
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Ingår i: Scandinavian Journal of Public Health. - : Sage Publications. - 1403-4948 .- 1651-1905. ; 46:8, s. 859-866
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Clinical experience suggests that patients with coeliac disease (CD) are more prone to develop herpes zoster (HZ), but robust studies are lacking.Methods: We identified 29,064 patients with CD 1969-2008 using biopsy report data from Sweden's 28 pathology departments. CD was equalled to villous atrophy (Marsh histopathology grade III). Each patient was matched on age, sex, calendar year and county of residence to up to five reference individuals (n=144,342) from the general population. We then used Cox regression to estimate hazard ratios (HRs) for future HZ (defined as having a hospital-based inpatient or outpatient record of this diagnosis in the Swedish Patient Register).Results: During follow-up, 154 (0.53%) individuals with CD and 499 (0.35%) reference individuals developed HZ. Among individuals aged >= 60 years, 1.06% of CD individuals and 0.85% of reference individuals had a lifetime record of HZ. Overall, CD was associated with a 1.62-fold increased risk of HZ (95% CI=1.35-1.95), and was seen also when we considered comorbidity with lymphoproliferative disease, systemic lupus erythematosus, type 1 diabetes, thyroid disease, rheumatoid disease and excluded individuals with a record of dermatitis herpetiformis. The increased risk remained significant after more than five years of follow-up (1.46; 1.16-1.84)Conclusions: CD is associated with HZ, the increased relative risk persists over time from celiac diagnosis but the absolute risk is small.
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| 22. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 23. |
- Pepitone, Kevin, Dr, 1988-, et al.
(författare)
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Design and Fabrication of a Canted-Cosine-Theta Double Aperture Orbit Corrector Dipole for the LHC
- 2023
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Ingår i: IEEE transactions on applied superconductivity (Print). - : IEEE. - 1051-8223 .- 1558-2515. ; 33:5
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Tidskriftsartikel (refereegranskat)abstract
- A prototype CCT dipole magnet developed by a collaboration between Swedish universities, Swedish industry and CERN will be tested at Uppsala University. This 1 m long double-aperture magnet can provide a field strength of 3.3 T at 85 A in a 70 mm aperture with an integrated field of 2.8 Tm. It is intended to replace the current LHC orbit corrector magnets which are reaching the end of their expected life due to the radiation load. The new magnet is designed to handle the radiation dose of the upgrade to the high-luminosity LHC, which will deliver about ten times the current radiation dose. It must therefore be more resistant to radiation and meet strict requirements in terms of electrical insulation while matching the original field quality and self-protective capability, mechanical volume, and maximum excitation current. This paper will present the latest of the design and manufacturing work, including the results of simulations of the mechanical field and the mechanical stress. Details of the various tests performed before machining the parts are also presented.
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| 24. |
- Postmus, Iris, et al.
(författare)
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Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
- 2014
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
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| 25. |
- Rupert, Deborah, 1986, et al.
(författare)
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Dual-Wavelength Surface Plasmon Resonance for Determining the Size and Concentration of Sub-Populations of Extracellular Vesicles
- 2016
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 88:20, s. 9980-9988
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Tidskriftsartikel (refereegranskat)abstract
- Accurate concentration determination of subpopulations of extracellular vesicles (EVs), such as exosomes, is of importance both in the context of understanding their fundamental biological role and of potentially using them as disease biomarkers. In principle, this can be achieved by measuring the rate of diffusion-limited mass uptake to a sensor surface modified with a receptor designed to only bind the subpopulation of interest. However, a significant error is introduced if the targeted EV subpopulation has a size, and thus hydrodynamic diffusion coefficient, that differs from the mean size and diffusion coefficient of the whole EV population and/or if the EVs become deformed upon binding to the surface. We here demonstrate a new approach to determine the mean size (or effective film thickness) of bound nanoparticles, in general, and EV subpopulation carrying a marker of interest, in particular. The method is based on operating surface plasmon resonance simultaneously at two wavelengths with different sensing depths and using the ratio of the corresponding responses to extract the particle size on the surface. By estimating in this way the degree of deformation of adsorbed EVs, we markedly improved their bulk concentration determination and showed that EVs carrying the exosomal marker CD63 correspond to not more than around 10% of the EV sample.
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| 26. |
- Sjöman, Henrik, et al.
(författare)
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Evaluation of Alnus subcordata for urban environments through assessment of drought and flooding tolerance
- 2021
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Ingår i: Dendrobiology. - : Bogucki Wydawnictwo Naukowe. - 1641-1307. ; 85, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- The urban environment is stressful and trees experience multiple stresses, including drought, flooding, and extreme heat, all of which are likely to increase under future climate warming and increasing urbanisation. In the selection of tree species to maximise ecosystem services, tolerance to site characteristics such as flooding and severe drought is of critical importance. This study evaluated the suitability of a rare species, Mims subcordata C.A. Mey (Caucasian alder) from the Hyrcanian forests of southern Azerbai-jan, for its functionality as an urban tree. A total of 48 pot-grown, two-year-old saplings of A. subcordata were tested in a greenhouse experiment using a complete randomised block design. Each block contained four replicates of three treatments (waterlogging, drought, control), with 16 plants per treatment. Height differences between treatments were measured, and water status was estimated by determination of midday leaf water potential (psi(L)) and stomatal conductance (g(s)). To estimate drought tolerance reaction in the treatments, leaf water potential at turgor loss (psi(P0)) was used together with broken-stick modelling of water status over time. A. subcordata plants showed no height increase, while plants in both the waterlogged and control treatments increased in height during the nine-week experiment. Over 63 days of flooding, plant water status was slightly more negative in the waterlogging treatment, but did not deviate essentially from the control. In the drought treatment, plant water status rapidly deviated from the control. There was a significant difference in psi(P0) between treatments, with drought-treated plants showing the lowest value (-2.31 MPa). This study demonstrated that A. subcordata has limited tolerance to drought and seems to rely more on water loss-avoiding strategies. However, the species may be usable at periodically waterlogged sites, due to its high tolerance to flooding. It could therefore be recommended for wet urban environments and stormwater management facilities, for which reliable guidance on suitable trees is currently lacking.
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