| 1. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 2. |
- 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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| 3. |
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| 4. |
- Ameli, A. A., et al.
(författare)
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Hillslope permeability architecture controls on subsurface transit time distribution and flow paths
- 2016
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Ingår i: Journal of Hydrology. - : Elsevier B.V.. - 0022-1694 .- 1879-2707. ; 543, s. 17-30
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Tidskriftsartikel (refereegranskat)abstract
- Defining the catchment transit time distribution remains a challenge. Here, we used a new semi-analytical physically-based integrated subsurface flow and advective–dispersive particle movement model to assess the subsurface controls on subsurface water flow paths and transit time distributions. First, we tested the efficacy of the new model for simulation of the observed groundwater dynamics at the well-studied S-transect hillslope (Västrabäcken sub-catchment, Sweden). This system, like many others, is characterized by exponential decline in saturated hydraulic conductivity and porosity with soil depth. The model performed well relative to a tracer-based estimate of transit time distribution as well as observed groundwater depth–discharge relationship within 30 m of the stream. Second, we used the model to assess the effect of changes in the subsurface permeability architecture on flow pathlines and transit time distribution in a set of virtual experiments. Vertical patterns of saturated hydraulic conductivity and porosity with soil depth significantly influenced hillslope transit time distribution. Increasing infiltration rates significantly decreased mean groundwater age, but not the distribution of transit times relative to mean groundwater age. The location of hillslope hydrologic boundaries, including the groundwater divide and no-flow boundary underlying the hillslope, changed the transit time distribution less markedly. These results can guide future decisions on the degree of complexity that is warranted in a physically-based rainfall–runoff model to efficiently and explicitly estimate time invariant subsurface pathlines and transit time distribution.
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| 5. |
- Ameli, A. A., et al.
(författare)
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The exponential decline in saturated hydraulic conductivity with depth : a novel method for exploring its effect on water flow paths and transit time distribution
- 2016
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Ingår i: Hydrological Processes. - : Wiley. - 0885-6087 .- 1099-1085. ; 30:14, s. 2438-2450
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Tidskriftsartikel (refereegranskat)abstract
- The strong vertical gradient in soil and subsoil saturated hydraulic conductivity is characteristic feature of the hydrology of catchments. Despite the potential importance of these strong gradients, they have proven difficult to model using robust physically based schemes. This has hampered the testing of hypotheses about the implications of such vertical gradients for subsurface flow paths, residence times and transit time distribution. Here we present a general semi-analytical solution for the simulation of 2D steady-state saturated-unsaturated flow in hillslopes with saturated hydraulic conductivity that declines exponentially with depth. The grid-free solution satisfies mass balance exactly over the entire saturated and unsaturated zones. The new method provides continuous solutions for head, flow and velocity in both saturated and unsaturated zones without any interpolation process as is common in discrete numerical schemes. This solution efficiently generates flow pathlines and transit time distributions in hillslopes with the assumption of depth-varying saturated hydraulic conductivity. The model outputs reveal the pronounced effect that changing the strength of the exponential decline in saturated hydraulic conductivity has on the flow pathlines, residence time and transit time distribution. This new steady-state model may be useful to others for posing hypotheses about how different depth functions for hydraulic conductivity influence catchment hydrological response.
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| 6. |
- Ali, Genevieve, et al.
(författare)
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Comparison of threshold hydrologic response across northern catchments
- 2015
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Ingår i: Hydrological Processes. - : Wiley. - 0885-6087 .- 1099-1085. ; 29:16, s. 3575-3591
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Tidskriftsartikel (refereegranskat)abstract
- Nine mid-latitude to high-latitude headwater catchments - part of the Northern Watershed Ecosystem Response to Climate Change (North-Watch) programme - were used to analyze threshold response to rainfall and snowmelt-driven events and link the different responses to the catchment characteristics of the nine sites. The North-Watch data include daily time-series of various lengths of multiple variables such as air temperature, precipitation and discharge. Rainfall and meltwater inputs were differentiated using a degree-day snowmelt approach. Distinct hydrological events were identified, and precipitation-runoff response curves were visually assessed. Results showed that eight of nine catchments showed runoff initiation thresholds and effective precipitation input thresholds. For rainfall-triggered events, catchment hydroclimatic and physical characteristics (e.g. mean annual air temperature, median flow path distance to the stream, median sub-catchment area) were strong predictors of threshold strength. For snowmelt-driven events, however, thresholds and the factors controlling precipitation-runoff response were difficult to identify. The variability in catchments responses to snowmelt was not fully explained by runoff initiation thresholds and input magnitude thresholds. The quantification of input intensity thresholds (e.g. snow melting and permafrost thawing rates) is likely required for an adequate characterization of nonlinear spring runoff generation in such northern environments.
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| 7. |
- Ameli, Ali A., et al.
(författare)
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Primary weathering rates, water transit times, and concentration-discharge relations : A theoretical analysis for the critical zone
- 2017
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Ingår i: Water resources research. - : AMER GEOPHYSICAL UNION. - 0043-1397 .- 1944-7973. ; 53:1, s. 942-960
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Tidskriftsartikel (refereegranskat)abstract
- The permeability architecture of the critical zone exerts a major influence on the hydrogeochemistry of the critical zone. Water flow path dynamics drive the spatiotemporal pattern of geochemical evolution and resulting streamflow concentration-discharge (C-Q) relation, but these flow paths are complex and difficult to map quantitatively. Here we couple a new integrated flow and particle tracking transport model with a general reversible Transition State Theory style dissolution rate law to explore theoretically how C-Q relations and concentration in the critical zone respond to decline in saturated hydraulic conductivity (K-s) with soil depth. We do this for a range of flow rates and mineral reaction kinetics. Our results show that for minerals with a high ratio of equilibrium concentration ( Ceq) to intrinsic weathering rate ( Rmax), vertical heterogeneity in K-s enhances the gradient of weathering-derived solute concentration in the critical zone and strengthens the inverse stream C-Q relation. As CeqRmax decreases, the spatial distribution of concentration in the critical zone becomes more uniform for a wide range of flow rates, and stream C-Q relation approaches chemostatic behavior, regardless of the degree of vertical heterogeneity in K-s. These findings suggest that the transport-controlled mechanisms in the hillslope can lead to chemostatic C-Q relations in the stream while the hillslope surface reaction-controlled mechanisms are associated with an inverse stream C-Q relation. In addition, as CeqRmax decreases, the concentration in the critical zone and stream become less dependent on groundwater age (or transit time).
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| 8. |
- Seibert, Jan, et al.
(författare)
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Groundwater dynamics along a hillslope : A test of the steady state hypothesis
- 2003
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Ingår i: Water resources research. - 0043-1397 .- 1944-7973. ; 39:1, s. 1014-
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Tidskriftsartikel (refereegranskat)abstract
- [1] Appropriate conceptual simplifications and assumptions are a central issue for hydrological modeling, especially when those models serve as the foundation for more complex hydrochemical or ecological models. A common and often unexamined assumption in conceptual modeling is that the relation between groundwater levels and runoff can be described as a succession of steady state conditions. This results in a single-valued, monotonic function between the groundwater levels and runoff. Consequently, the simulated rise and fall in groundwater levels always follow the dynamics of runoff. We tested this assumption with an analysis of detailed groundwater level data along two opposing hillslopes along a stream reach in a Swedish till catchment at Svartberget. Groundwater levels in areas close to the stream followed the dynamics of the runoff. The correlation between groundwater level and runoff decreased markedly for wells farther than approximately 40 m from the stream. The levels were often independent of streamflow: Upslope area groundwater could be rising when riparian groundwater and runoff were falling, and vice versa. There was a high degree of correlation between groundwater levels at similar distances from the stream. The median Spearman rank correlation between wells within 35 m from the stream was 0.86 and for wells located more than 60 m from the stream was 0.96. This indicated that there is a common hydrological pattern even in the upslope area that can be identified and modeled. Despite the widespread acceptance of the steady state assumption previously in this and other study catchments, our study shows that it is not valid for the investigated hillslope site. If the divergence from steady state, with potential ramifications for other processes such as runoff chemistry, is common, then it will be worthwhile to reconsider the appropriate range of applicability for the steady state hypothesis, and the alternatives to that hypothesis.
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