| 1. |
- Barrett, Jennifer H., et al.
(författare)
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Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:6, s. 1351-1360
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Tidskriftsartikel (refereegranskat)abstract
- At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the missing heritability. What's new? In genome-wide association studies, researchers identify genetic variants that frequently associate with a particular disease, though the variants identified may not contribute to the molecular cause of the disease. This study took a closer look at 17 regions associated with melanoma, fine mapping the regions both in people with melanoma and in healthy controls. Though single SNPs account for the association in some regions, they found that in a few regions, several SNPs - and possibly multiple genes - contributed to the association signal. These findings illustrate the importance of not overlooking the interaction between multiple genetic markers when conducting such studies.
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| 2. |
- Barrett, Jennifer H., et al.
(författare)
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Genome-wide association study identifies three new melanoma susceptibility loci
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1108-1113
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 x 10(-9)), an SNP in MX2 (rs45430, P = 2.9 x 10-9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 x 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 x 10(-7) under a fixed-effects model and P = 1.2 x 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
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| 3. |
- Bishop, D. Timothy, et al.
(författare)
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Genome-wide association study identifies three loci associated with melanoma risk
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:8, s. 920-925
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.
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| 4. |
- Duffy, DL, et al.
(författare)
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Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 299-
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Tidskriftsartikel (refereegranskat)abstract
- The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
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| 5. |
- Iles, Mark M., et al.
(författare)
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A variant in FTO shows association with melanoma risk not due to BMI
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:4, s. 428-432
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Tidskriftsartikel (refereegranskat)abstract
- We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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| 6. |
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| 7. |
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| 8. |
- 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
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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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| 9. |
- Malmström, Rickard E., et al.
(författare)
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Dabigatran - a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs
- 2013
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Ingår i: Frontiers in Pharmacology. - : FRONTIERS RESEARCH FOUNDATION. - 1663-9812. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies have shown dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. There are also issues with potentially re-designing anticoagulant services. This has resulted in activities across countries to better manage its use. Objective: To (i) review authority activities in over 30 countries and regions, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications for all major stakeholder groups. Methodology: Descriptive review and appraisal of activities regarding dabigatran and the development of guidance for groups through an iterative process. Results: There has been a plethora of activities among authorities to manage the prescribing of dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions, and monitoring of prescribing post-launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where there are concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.
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| 10. |
- Rafnar, Thorunn, et al.
(författare)
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European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.
- 2011
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 20:21, s. 4268-81
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Tidskriftsartikel (refereegranskat)abstract
- Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.
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| 11. |
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| 12. |
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| 13. |
- Abbott, Benjamin W., et al.
(författare)
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Biomass offsets little or none of permafrost carbon release from soils, streams, and wildfire : an expert assessment
- 2016
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- As the permafrost region warms, its large organic carbon pool will be increasingly vulnerable to decomposition, combustion, and hydrologic export. Models predict that some portion of this release will be offset by increased production of Arctic and boreal biomass; however, the lack of robust estimates of net carbon balance increases the risk of further overshooting international emissions targets. Precise empirical or model-based assessments of the critical factors driving carbon balance are unlikely in the near future, so to address this gap, we present estimates from 98 permafrost-region experts of the response of biomass, wildfire, and hydrologic carbon flux to climate change. Results suggest that contrary to model projections, total permafrost-region biomass could decrease due to water stress and disturbance, factors that are not adequately incorporated in current models. Assessments indicate that end-of-the-century organic carbon release from Arctic rivers and collapsing coastlines could increase by 75% while carbon loss via burning could increase four-fold. Experts identified water balance, shifts in vegetation community, and permafrost degradation as the key sources of uncertainty in predicting future system response. In combination with previous findings, results suggest the permafrost region will become a carbon source to the atmosphere by 2100 regardless of warming scenario but that 65%-85% of permafrost carbon release can still be avoided if human emissions are actively reduced.
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| 14. |
- Amvrosiadi, Nino, et al.
(författare)
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Soil moisture storage estimation based on steady vertical fluxes under equilibrium
- 2017
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Ingår i: Journal of Hydrology. - : Elsevier B.V.. - 0022-1694 .- 1879-2707. ; 553, s. 798-804
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Tidskriftsartikel (refereegranskat)abstract
- Soil moisture is an important variable for hillslope and catchment hydrology. There are various computational methods to estimate soil moisture and their complexity varies greatly: from one box with vertically constant volumetric soil water content to fully saturated-unsaturated coupled physically-based models. Different complexity levels are applicable depending on the simulation scale, computational time limitations, input data and knowledge about the parameters. The Vertical Equilibrium Model (VEM) is a simple approach to estimate the catchment-wide soil water storage at a daily time-scale on the basis of water table level observations, soil properties and an assumption of hydrological equilibrium without vertical fluxes above the water table. In this study VEM was extended by considering vertical fluxes, which allows conditions with evaporation and infiltration to be represented. The aim was to test the hypothesis that the simulated volumetric soil water content significantly depends on vertical fluxes. The water content difference between the no-flux, equilibrium approach and the new constant-flux approach greatly depended on the soil textural class, ranging between ∼1% for silty clay and ∼44% for sand at an evapotranspiration rate of 5 mm·d−1. The two approaches gave a mean volumetric soil water content difference of ∼1 mm for two case studies (sandy loam and organic rich soils). The results showed that for many soil types the differences in estimated storage between the no-flux and the constant flux approaches were relatively small.
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| 15. |
- Amvrosiadi, Nino
(författare)
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The value of experimental data and modelling for exploration of hydrological functioning: The case of a till hillslope
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Successfully modeling one system response (e.g. hydrograph or solute transport) sometimes gives the false sense of well-characterizing the modeled system. This is partly because of the well-known equifinality issue; during the calibration process multiple parameter combinations can produce similarly good results. One step forward towards a better-defined system is using measured (at relevant scale) values for the model parameters, as well as using multiple conditions to constrain the model.But when not enough, or relevant, field measurements are available, virtual experiments (VE’s) can be used as a supplementary method to model calibration. The advantage of VE’s over model calibration is that they can also be used to explore assumptions both on the system hydrological processes, and on the model structure.One goal of this study was to utilize both field measurements and models for better characterization of the S-transect hillslope, located in Västrabäcken catchment, Northern Sweden. This included (a) characteristics in space: system vertical boundaries, hydraulic parameters, pore water velocity distribution, spatial correlation of flowpaths, soil water retention properties; (b) characteristic of system’s dynamic behavior: storage – discharge relationship, transit time distribution, turnover time; and (c) outputs’ sensitivity to external forcing, and to small scale structure assumptions. The second goal was to comment on the value of field measurements and virtual experiments for extracting information about the studied system.An intensely monitored study hillslope was chosen for this work. Although the hillslope has already been the subject of multiple field and modelling studies, there are still open questions regarding the characteristics listed above. The models used were the Vertical Equilibrium Model (VEM), and the Multiple Interacting Pathways (MIPs) model.It was found that the hillslope was well connected; from the near-stream areas up to the water divide the storage – discharge relationship could be described as an exponential function. Also, the dynamic storage (which controls the hydrograph dynamics) was much smaller comparing to the total hillslope storage. The unsaturated soil storage was found to be more sensitive to water table positions than vertical flux magnitude. The dynamic condition of external forcing (precipitation and evapotranspiration) affected the transit time distribution (TTD) shape. And, opposite to expectations, TTD was not sensitive to micro-scale structural assumptions tested here.
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| 16. |
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| 17. |
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| 18. |
- Amvrosiadi, Nino, et al.
(författare)
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Water storage dynamics in a till hillslope : the foundation for modeling flows and turnover times
- 2017
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Ingår i: Hydrological Processes. - : John Wiley and Sons Ltd. - 0885-6087 .- 1099-1085. ; 31:1, s. 4-14
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Tidskriftsartikel (refereegranskat)abstract
- Studies on hydrology, biogeochemistry, or mineral weathering often rely on assumptions about flow paths, water storage dynamics, and transit times. Testing these assumptions requires detailed hydrometric data that are usually unavailable at the catchment scale. Hillslope studies provide an alternative for obtaining a better understanding, but even on such well-defined and delimited scales, it is rare to have a comprehensive set of hydrometric observations from the water divide down to the stream that can constrain efforts to quantify water storage, movement, and turnover time. Here, we quantified water storage with daily resolution in a hillslope during the course of almost an entire year using hydrological measurements at the study site and an extended version of the vertical equilibrium model. We used an exponential function to simulate the relationship between hillslope discharge and water table; this was used to derive transmissivity profiles along the hillslope and map mean pore water velocities in the saturated zone. Based on the transmissivity profiles, the soil layer transmitting 99% of lateral flow to the stream had a depth that ranged from 8.9 m at the water divide to under 1 m closer to the stream. During the study period, the total storage of this layer varied from 1189 to 1485 mm, resulting in a turnover time of 2172 days. From the pore water velocities, we mapped the time it would take a water particle situated at any point of the saturated zone anywhere along the hillslope to exit as runoff. Our calculations point to the strengths as well as limitations of simple hydrometric data for inferring hydrological properties and water travel times in the subsurface.
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| 19. |
- Bishop, Kevin, et al.
(författare)
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A primer for hydrology : the beguiling simplicity of Water's journey from rain to stream at 30 Preface
- 2015
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Ingår i: Hydrological Processes. - : Wiley. - 0885-6087 .- 1099-1085. ; 29:16, s. 3443-3446
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Water's journey from rain to stream by Harald Grip and Allan Rodhe (1985, in Swedish: Vattnets vag fran regn till back) was one of the first textbooks to present groundwater contributions as a major feature of runoff generation, with implications for water quality and management. Three decades later, we have the privilege of presenting a special issue of Hydrological Processes, Runoff Generation in a Nordic Light: 30Years with Water's Journey from Rain to Stream' that seeks to introduce the book to a larger audience and continue the journey of ideas that the authors set in motion with their book.
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| 20. |
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| 21. |
- Bishop, Kevin, et al.
(författare)
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Effect of DEM-smoothing and -aggregation on topographically-based flow directions and catchment boundaries
- 2021
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Ingår i: Journal of Hydrology. - : Elsevier BV. - 0022-1694 .- 1879-2707. ; 602
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Tidskriftsartikel (refereegranskat)abstract
- It is generally assumed that, in humid climates, the groundwater table is a subdued copy of the surface topography. However, the general groundwater table is unlikely to be affected by the microtopography as seen in high-resolution Digital Elevation Models (DEMs). So far, there has been little guidance on the best resolution DEM to use to determine the shape of the water table or the direction of shallow groundwater flow in headwater catchments. We, therefore, looked at the effects of DEM-smoothing and -aggregation on the calculated flow directions and derived catchment boundaries, and identified areas and landscape features for which the calculated flow directions are particularly sensitive to DEM smoothing or aggregation. For > 40 % of the area of the Krycklan study catchment, the calculated flow directions depend strongly on the degree of smoothing or aggregation of the DEM. The four main landscape features for which DEM smoothing or aggregation strongly affected the calculated flow directions were: local slopes in the opposite direction of the general slope, flat areas, ridges, and incised streambanks. To determine the effects of the changing flow directions on the derived catchment boundaries for the smoothed and aggregated DEMs, we calculated the drainage area for 40 locations, representing the outlets of catchments of varying sizes. The shape and size of the catchments of first-order streams were most affected by the processing of the DEM. These streams were often almost completely smoothed out during the DEM preprocessing steps. These shifts in catchment boundaries and drainage area would have a large effect on the water balance. This study thus highlights the need to carefully consider the effects of DEM smoothing or -aggregation on the calculated flow directions and drainage areas.
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| 22. |
- Buffam, Ishi, et al.
(författare)
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Spatial heterogeneity of the spring flood acid pulse in a boreal stream network.
- 2008
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 407:1, s. 708-22
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Tidskriftsartikel (refereegranskat)abstract
- Spatial and temporal patterns in streamwater acidity are ecologically important, but difficult to measure in parallel. Here we present the spatial distribution of streamwater chemistry relevant to acidity from 60 stream sites distributed throughout a 67 km(2) boreal catchment, sampled during a period of winter baseflow (high pH) and during a spring flood episode (low pH). Sites were grouped based on pH level and pH change from winter baseflow to spring flood. The site attributes of each pH group were then assessed in terms of both stream chemistry and subcatchment landscape characteristics. Winter baseflow pH was high throughout most of the stream network (median pH 6.4), but during the spring flood episode stream sites experienced declines in pH ranging from 0-1.6 pH units, resulting in pH ranging from 4.3-6.3. Spring flood pH was highest in larger, lower altitude catchments underlain by fine sorted sediments, and lowest in small, higher altitude catchments with a mixture of peat wetlands and forested till. Wetland-dominated headwater catchments had low but stable pH, while the spring flood pH drop was largest in a group of catchments of intermediate size which contained well-developed coniferous forest and a moderate proportion of peat wetlands. There was a trend with distance downstream of higher pH, acid neutralizing capacity (ANC) and base cation concentrations together with lower dissolved organic carbon (DOC, strongly negatively correlated with pH). This apparent scale-dependence of stream chemistry could be explained by a number of environmental factors which vary predictably with altitude, catchment area and distance downstream-most notably, a shift in surficial sediment type from unsorted till and peat wetlands to fine sorted sediments at lower altitudes in this catchment. As a result of the combination of spatial heterogeneity in landscape characteristics and scale-related processes, boreal catchments like this one can be expected to experience high spatial variability both in terms of chemistry at any given point in time, and in the change experienced during high discharge episodes. Although chemistry patterns showed associations with landscape characteristics, considerable additional variability remained, suggesting that the modeling of dynamic stream chemistry from map parameters will continue to present a challenge. (C) 2008 Elsevier B.V. All rights reserved.
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| 23. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 24. |
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| 25. |
- Edström, Kristina, et al.
(författare)
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Carbon electrode morphology and thermal stability of the passivation layer.
- 2001
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Ingår i: J. Power Sources. - 0378-7753. ; 97-98, s. 87-
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Tidskriftsartikel (refereegranskat)abstract
- Thermal stability of the solid electrolyte interface (SEI)-layers formed on graphite, mesocarbon microbeads and carbon-black anodes is shown to be dependent on the type lithium salt used in the electrolyte. Exothermic breakdown of the passivation layers
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