| 1. |
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| 2. |
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| 3. |
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| 4. |
- Dumanski, Jan P., et al.
(författare)
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Smoking is associated with mosaic loss of chromosome Y
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6217, s. 81-83
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Tidskriftsartikel (refereegranskat)abstract
- Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared to females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.
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| 5. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 6. |
- Forsberg, Lars A., et al.
(författare)
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Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:6, s. 624-628
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Tidskriftsartikel (refereegranskat)abstract
- Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained(1,2). Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells(3,4), but the phenotypic consequences of LOY have been elusive(5-10). From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
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| 7. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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| 8. |
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| 9. |
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| 10. |
- Molin, Nils-Erik, et al.
(författare)
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Eigenmodes of av violin body
- 1990
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Ingår i: Proceedings / Nordic Acoustical Meeting 90 - NAM 90. - Luleå : CENTEK. - 9186998390 ; , s. 421-428
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Konferensbidrag (refereegranskat)
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| 11. |
- Molin, Nils-Erik, et al.
(författare)
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Parameters of violin plates and their influence on the plate modes
- 1988
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Ingår i: Journal of the Acoustical Society of America. - : Acoustical Society of America (ASA). - 0001-4966 .- 1520-8524. ; 83:1, s. 281-291
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Tidskriftsartikel (refereegranskat)abstract
- Noncontact measuring methods and numerical calculations are used in a study of musical instruments. First, a simple method to determine the material parameters of a blank to a violin plate is presented. Eigenmodes of rectangular free-free violin wooden blanks are determined using optical nondestructive methods, Chladni patterns, or tapping. Assuming orthotropic material, the first three eigenmodes for such a blank are calculated using the finite element method (FEM). It is shown that the frequency of each eigenmode depends on separate elastic parameters. With this one variable dependence, it is a simple task to determine effective material parameters for quarter-cut standard wooden blanks when the frequencies and mass are known. Second, the violin maker's problem with the influence of material and geometrical parameters on the vibration modes is investigated. Numerical models and corresponding real violin plates are made from the spruce and the maple blanks. Good agreement between calculated and experimentally obtained plate modes is found. Calculations with a 10% variation in each parameter are thereafter used to give information about the influence of overall plate thickness variation, of local thickness variations, of changes in arch-height, and of material parameters. Third, boundary conditions for the plates when glued to the ribs are examined in a pilot experiment.
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| 12. |
- Nikpay, Majid, et al.
(författare)
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
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Tidskriftsartikel (refereegranskat)abstract
- Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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| 13. |
- Steffenburg-Nordenström, Joachim, 1962-
(författare)
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Process chain simulation of forming, welding and heat treatment of Alloy 718
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Manufacturing of aero engine components requires attention to residual stress and final shape of the product in order to meet high quality product standards.This sets very high demands on involved manufacturing steps to meet design requirements. Simulation of manufacturing processes can therefore be animportant tool to contribute to quality assurance.The focus in this work is on simulation of a manufacturing process chain comprising of sheet metal forming, welding and a stress relief heat treatment.Simulation of sheet metal forming can be used to design a forming tool design that accounts for the material behaviour, e.g. spring back, and avoid problems such as wrinkling, thinning and cracking. Moreover, the simulation can also show how the material is stretched and work hardened. The residual stresses after forming may be of local character or global depending on the shape that is formed. However, the heat affected zone due to welding is located near the weld.The weld also causes large residual stresses with the major component along the weld. It is found that the magnitude of the residual stresses after welding is affected by remaining stresses from the previous sheet metal forming. The final stress relieve treatment will relax these residual stresses caused by e.g. forming and welding. However, this causes additional deformations.The main focus of this study is on how a manufacturing process step affects the subsequent step when manufacturing a component of the nickel-based super alloy 718. The chosen route and geometry is a simplified leading edge of an exhaust case guide vane. The simulations were validated versus experiments. The computed deformations were compared with measurements after each manufacturing step. The overall agreement between experiments and measurement was good. However, not sufficiently accurate considering the required tolerance of the component. It was found from simulations that the residual stresses after each process affects the subsequent step. After a complete manufacturing process chain which ends with a stress relief heat treatment the residual stresses were not negligible. VIII Special experiments were performed for studying the stress relief in order to understand how the stresses evolve through the heat treatment cycle during relaxation. It was found that the stresses were reduced already during the beginning of the heating up sequence due to decreasing Young´s modulus and yield stress with increasing temperature. Relaxation due to creep starts when a certain temperature was reached which gave a permanent stress relief.
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| 14. |
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| 15. |
- Börjesson, Lars, et al.
(författare)
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Residual stresses and microstructure computation for multipass [multirun] welding
- 1997
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Ingår i: The Fifth International Conference on Residual Stresses - ICRS-5. - Linköping : Linköping University Electronic Press. - 9172192100 ; , s. 189-194
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Konferensbidrag (refereegranskat)abstract
- Residual stress studies (by centre-hole drilling and finite element analysis) and microstructural computations (using temperature measurements) were carried out on multirun butt welded steel plates. The plates, 200 mm thickness, were in SIS 2134 material (0.12%C, 1.42%Mn, 0.044%V, 0.014%Ti, 0.038%Al). Welding was by submerged arc welding using ESAB OK AUTROD 12.10 filler material and ESAB OK FLUX 10.80 flux
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| 16. |
- Börjesson, Lars, et al.
(författare)
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Simulation of multipass welding using mixture rules for prediction of material properties
- 1998
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Ingår i: Simulation of materials processing : theory, methods and applications. - Rotterdam : Balkema Publishers, A.A. / Taylor & Francis The Netherlands. - 905410970X ; , s. 351-357
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Konferensbidrag (refereegranskat)abstract
- Multipass butt welding of two 0.2 m thick steel plates has been investigated. The purpose of the project is to evaluate the residual stresses by experiment and simulations. Temperature dependent material properties were assumed in previous studies. We account for the dependency on temperature history in this work. This has been done by computing the microstructure evolution. This is combined with mixture rules for computing material properties.
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| 17. |
- Börjesson, Lars, et al.
(författare)
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Simulation of multipass welding with simultaneous computation of material properties
- 2001
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Ingår i: Journal of engineering materials and technology. - : ASME International. - 0094-4289 .- 1528-8889. ; 123:1, s. 106-111
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Tidskriftsartikel (refereegranskat)abstract
- Multipass butt welding of two 0.2 m thick steel plates has been investigated. The objective is to calculate residual stresses and compare them with measured residual stresses. The material properties depend on temperature and temperature history. This dependency is accounted for by computing the microstructure evolution and using this information for computing material properties. This is done by assigning temperature dependent material properties to each phase and applying mixture rules to predict macro material properties. Two different materials have been used for the microstructure calculation, one for the base material and one for the filler material
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| 18. |
- Chen, X., et al.
(författare)
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A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
- 2018
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1809-1818
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.
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| 19. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 20. |
- Domkin, Konstantin, et al.
(författare)
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Physically based material model in sheet metal forming
- 2001
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Ingår i: Simulation of materials processing. - Lisse : Balkema Publishers, A.A. / Taylor & Francis The Netherlands. - 9026518226 ; , s. 221-226
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Konferensbidrag (refereegranskat)
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| 21. |
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| 22. |
- Eriksson, Mikael, et al.
(författare)
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MAX-IV Design: Pushing the Envelope
- 2007
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Ingår i: 2007 IEEE Particle Accelerator Conference, vols 1-11. - 9781424409167 ; , s. 1277-1279
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Konferensbidrag (refereegranskat)abstract
- The proposed MAX IV facility is meant as a successor to the existing MAX-lab. The accelerator part will consist of three storage rings, two new ones operated at 3 and 1.5 GeV respectively and the existing 700 MeV MAX III ring. The two new rings have identical lattices and are placed on top of each other. Both these rings have a very small emittance, 0.86 and 0.4 nm rad respectively, and offer synchrotron radiation of very high mean brilliance. As an injector, a 3 GeV linear accelerator is planned. The design philosophy and the special technical solutions called for are presented in this paper.
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| 23. |
- Eriksson, Mikael, et al.
(författare)
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MAX4, a 3 GeV light source with a flexible injector
- 2002
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Ingår i: 8th European Particle Accelerator Conference. ; , s. 686-687
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Konferensbidrag (refereegranskat)abstract
- The MAX4 ring is intended to be the future user facility at MAXlab. The high-brilliance 3 GeV storage ring, equipped with small gap, short period superconducting undulators, demonstrates a high mean brilliance over a wide photon energy spectrum. The ring itself is defined from the routine operation of the small gap insertion devices, which is reflected in the small aperture of the ring magnets. The development of future light sources, like the free electron laser and energy recovery systems, opens up new challenging possibilities to create high brilliance, short pulse radiation. This development is today far from being mature, a strong development of new ideas and techniques will most probably take place during the next decade(s). The MAX4 full-energy injector is constructed to incorporate these future developments. The proposed 3 GeV energy recovery race-track microtron will open up the possibility of topping up injection and to deliver Fourier transform limited spontaneous as well as coherent radiation up to the hard X-ray spectral region
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| 24. |
- Eriksson, Mikael, et al.
(författare)
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STATUS OF THE MAX IV LIGHT SOURCE PROJECT
- 2006
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Ingår i: European Particle Accelerator Conference 2006, Edinburgh, UK.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 25. |
- Eriksson, Mikael, et al.
(författare)
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The MAX IV Synchrotron Light Source
- 2011
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Ingår i: [Host publication title missing]. - 9789290833666 ; , s. 3026-3028
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Konferensbidrag (refereegranskat)abstract
- The MAX IV synchrotron radiation facility is currently being constructed in Lund, Sweden. It consists of a 3 GeV linac injector and 2 storage rings operated at 1.5 and 3 GeV respectively. The linac injector will also be used for the generation of short X-ray pulses. The three machines mentioned above are described with some emphasis on the effort to create a very small emittance in the 3 GeV ring. Some unconventional technical solutions will also be presented.
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| 26. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 27. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 28. |
- Fällström, Karl-Evert, et al.
(författare)
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Transient bending waves in anisotropic plates studied by hologram interferometry
- 1989
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Ingår i: Experimental mechanics. - 0014-4851 .- 1741-2765. ; 29:4, s. 409-413
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Tidskriftsartikel (refereegranskat)abstract
- Propagating bending waves are studied in plates made of glass-fiber reinforced polyester. The waves are generated by the impact of a ballistic pendulum. Hologram interferometry, with a double pulsed ruby laser as light source, is used to record the out of plane motion of the waves. The interferograms have an elliptic-like symmetry for an orthotropic plate, while the wave pattern for a symmetric angle-ply reinforced plate has a symmetry about the axes of reinforcements. Experimental data are compared on one hand to analytical results obtained by assuming that the orthotropic plate can be described as if isotropic along the main axes, and on the other hand to numerical results from calculations using the finite-element method. The effective Young's modulus raised to power 1/4 is shown to be an important parameter for the description of the dispersive wave pattern. A defect in the plate alters the wave pattern in the interferograms significantly. This may have technical use.
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| 29. |
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| 30. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 31. |
- 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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| 32. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 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
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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| 33. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 34. |
- Lauridsen, Jonas, et al.
(författare)
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Deposition of Ti-Si-C-Ag nanocomposite coatings as electrical contact material
- 2010
-
Ingår i: Proceedings of the 56th IEEE Holm Conference on Electrical Contacts (HOLM). - : IEEE. - 9781424481743 ; , s. 288-294
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- This paper is a brief review of our recent work and a follow up study on nanocomposite coatings comprising nanocrystalline TiC embedded in an amorphous SiC matrix (nc-TiC/a-SiC) with and without Ag additions applied as electrical contacts. These coating materials are deposited at very high deposition rates (>10 μm/h), to meet industrial demands of high productivity. Here we consider Ti-Si-C-Ag nanocomposite coatings with Ag content in the range of 0-22 at.% deposited in a pilot-plant or an industrial deposition system by dc magnetron sputtering from compound targets onto Si(100) and SiO2(100) substrates. The microstructure, electrical, and mechanical properties of the coatings were studied with transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, electrical contact resistance, resistivity, and nanoindentation measurements. Varying the deposition parameters bias and pressure within ranges typical of coating processing had no effect on the structure. A variation was, however, observed for the contact resistance, that was determined to be in the range 400-900 mΩ at a contact force between 1.9-2.65 N. The coatings with highest Ag content had the lowest contactresistance.
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| 35. |
- LeBlanc, Gregory, et al.
(författare)
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MAX 4, A 3 GEV light source
- 2003
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Ingår i: Proceedings of the IEEE Particle Accelerator Conference. ; 4, s. 2321-2323
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Konferensbidrag (refereegranskat)abstract
- A proposal for a new synchrotron light source, MAX 4, is presented. The main components are two identical storage rings operated at different electron beam energies and equipped with superconducting insertion devices. Small beam emittances will yield high brilliance radiation over a wide spectral range. A small horizontal emittance is achieved by using a large number of cells with gradient dipoles flanked by horizontally focusing quadrupoles. A small magnet aperture allows strong gradients in dipoles and strong sextupole components in quadrupoles. This results in an equilibrium emittance on the order of 1 nmrad. A full-energy injector, enabling top-up operation, will be a 3 GeV S-band linac with an energy doubling system. This opens up the possibility to produce short, intense radiation pulses, coherent as well as spontaneous.
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| 36. |
- Lejon, Erik
(författare)
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Information Integration in Computer Aided Design
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Information management during product development and over the lifecycle of products has become central to enable competitiveness in the engineering industry. Reuse and integration of information is essential to avoid duplicating efforts. This need for methods and tools which effectively enable capture, retrieval, representation, and reuse of information.The research presented in this thesis is based on investigations of information management at two companies in the engineering industry in Sweden. One case at each company was identified. The cases focused on the methods and tools with which product-related information is captured, retrieved represented, and reused.The challenge lies in ensuring that pertinent product information can be efficiently captured and, once stored, can be understood, used, and reused by both systems and individuals.To address the challenge, an approach for integrating information in Product Development was developed, implemented, and evaluated. One of the bases of the approach is the information architecture used to provide easy access to product information in an integrated and customizable way. Information is stored in a main source, a Product Lifecycle Management (PLM) system tightly integrated with other sources. These tightly integrated information sources together form a PLM solution. The data model of the PLM system becomes the unified data model for the product information. The approach allows for redundancy-free storage that ensures that the information provided is up-to-date and valid. Ease of access to the information is provided by utilizing a service-oriented architecture to provide Web applications and integrations.Close collaboration between researchers and users has been essential throughout the entire process of investigation, implementation, and evaluation.Feedback from the evaluation showed that the prescribed approach was preferred to the old approach and that the participants from both companies agree that it will likely provide value to both authors and consumers of the information.
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| 37. |
- Lind, Lars, et al.
(författare)
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Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p '-dde levels in a population-based sample
- 2017
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Ingår i: Environment International. - Oxford, United Kingdom : Elsevier. - 0160-4120 .- 1873-6750. ; 98, s. 212-218
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p, p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.Results: Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472 ng/g lipid, while the corresponding level for those being homozygote for the T allelewas 192 ng/g lipid (p= 1.5x10(-31)). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19: 41520351; p= 2.2 x 10(-8)). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p= 6.2 x 10(-9)) located 7 kb downstreamthe CYP2B6 gene (cg27089200, position chr19: 41531976). This CpG-sitewas also related to the lead SNP (p = 3.8 x 10(-35)), but mediated only 4% of the effect of the lead SNP on p, p'-DDE levels.Conclusion: Circulating levels of p, p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p, p'-DDE levels.
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| 38. |
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| 39. |
- Lindgren, Michael, et al.
(författare)
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Roll Forming
- 2014
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Ingår i: Handbook of Manufacturing Engineering and Technology. - London : Encyclopedia of Global Archaeology/Springer Verlag. - 9781447149767 ; , s. 1-19
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Bokkapitel (refereegranskat)abstract
- Roll forming is cost-effective compared to other sheet metal forming processes for uniform profiles. The process has during the last 10 years developed into forming of profiles with varying cross sections and is thereby becoming more flexible. The motion of the rolls can now be controlled with respect to many axes enabling a large variation in the profiles along the formed sheet, the so-called 3D roll forming or flexible roll forming technology. The roll forming process has also advantages compared to conventional forming for high-strength materials. Furthermore, computer tools supporting the design of the process have also been developed during the last 10 years. This is quite important when designing the forming of complex profiles. The chapter describes the roll forming process, particularly from the designer’s perspective. It gives the basic understanding of the process and how it is designed. Furthermore, modern computer design and simulation tools are discussed.
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| 40. |
- Lindgren, Michael, et al.
(författare)
-
Roll Forming
- 2015
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Ingår i: Handbook of Manufacturing Engineering and Technology. - London : Encyclopedia of Global Archaeology/Springer Verlag. - 9781447146698 - 9781447146704 ; , s. 285-307
-
Bokkapitel (refereegranskat)abstract
- Roll forming is cost-effective compared to other sheet metal forming processes for uniform profiles. The process has during the last 10 years developed into forming of profiles with varying cross sections and is thereby becoming more flexible. The motion of the rolls can now be controlled with respect to many axes enabling a large variation in the profiles along the formed sheet, the so-called 3D roll forming or flexible roll forming technology. The roll forming process has also advantages compared to conventional forming for high-strength materials. Furthermore, computer tools supporting the design of the process have also been developed during the last 10 years. This is quite important when designing the forming of complex profiles. The chapter describes the roll forming process, particularly from the designer’s perspective. It gives the basic understanding of the process and how it is designed. Furthermore, modern computer design and simulation tools are discussed
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| 41. |
- Lindgren, Stig-Åke, 1950, et al.
(författare)
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Coverage-dependent frequency for Li-atom vibrations on Cu(111)
- 1996
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Ingår i: Physical Review B. - 2469-9969 .- 2469-9950. ; 54:15, s. 10912 - 10916
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Tidskriftsartikel (refereegranskat)abstract
- Electron-energy-loss spectra recorded for monolayer amounts of Li adsorbed on Cu(111) show a loss peak associated with Li vibrations perpendicular to the substrate. The loss energy shifts from 38 meV at low coverage to 43 meV at 0.3 ML and remains constant for coverages between 0.3 and 0.5 ML. The loss intensity passes a maximum at a Li coverage of 0.15 ML and gradually decreases such that it is difficult to resolve a loss peak at coverages above 0.5 ML. The high loss energy indicates that the adatom resides on the surfaces rather than in substitutional sites. The frequency shift is much too large to be explained by dipole-dipole interactions. The above results are obtained with the evaporation source loaded with the natural Li isotope mixture (92.6% 7Li, 7.4% 6Li). Measurements with 6Li show that the increase of the vibration frequency with increasing coverage is not an isotope effect.
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| 42. |
- Lu, Yingchang, et al.
(författare)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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| 43. |
- Mahajan, Anubha, et al.
(författare)
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Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
- 2015
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
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| 44. |
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| 45. |
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| 46. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Tidskriftsartikel (refereegranskat)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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| 47. |
- Skogseid, Britt, et al.
(författare)
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Operative tumor yield obviates preoperative pancreatic localization in multiple endocrine neoplasia type 1
- 1995
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Ingår i: Journal of Internal Medicine. - 0954-6820 .- 1365-2796. ; 238:3, s. 281-288
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Tidskriftsartikel (refereegranskat)abstract
- The efficiency of pancreatic tumour localization was prospectively evaluated in 12 consecutive patients with multiple endocrine neoplasia type 1 (MEN1), who were subjected to extirpation of 56 islet cell neoplasms of 0.2-4 cm in diameter (mean 0.8 cm) during pancreatic resection and enucleation. Computed tomography, angiography of the coeliac trunc and superior mesenteric artery, and percutaneous ultrasound correctly localized 7-12% of the tumours and 21-37% of the 19 lesions measuring at least one centimetre in diameter. Transhepatic portal vein sampling correctly located tumour sites in the proximal or distal portions of the pancreas in four out of six patients, but demonstrated unsatisfactory specificity. Intra-operative ultrasound and bidigital palpation of the pancreas had overall sensitivities of 86 and 45%, respectively, and eight lesions below 0.3 cm in diameter remained undetected with intraoperative ultrasound. It is concluded that diagnosis of endocrine pancreatic neoplasms is biochemical in MEN1 and that broad screening of tumour markers efficiently reveals pancreatic involvement decades before the development of a clinically overt disease. Intra-operative ultrasound is a requisite for pancreatic endocrine surgery in MEN1, and it obviates the need for conventional pancreatic imaging unless a pre-operative search for metastatic disease and anatomical aberrations is considered important.
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| 48. |
- Strawbridge, Rona J., et al.
(författare)
-
Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
- 2017
-
Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 266, s. 196-204
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
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| 49. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 50. |
- Surendran, Praveen, et al.
(författare)
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Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1151-1161
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Tidskriftsartikel (refereegranskat)abstract
- High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
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