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- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 3. |
- 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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- Van Loon, Anne F., et al.
(författare)
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Drought in a human-modified world : reframing drought definitions, understanding, and analysis approaches
- 2016
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Ingår i: Hydrology and Earth System Sciences. - : Copernicus GmbH. - 1027-5606 .- 1607-7938. ; 20:9, s. 3631-3650
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Tidskriftsartikel (refereegranskat)abstract
- In the current human-modified world, or Anthropocene, the state of water stores and fluxes has become dependent on human as well as natural processes. Water deficits (or droughts) are the result of a complex interaction between meteorological anomalies, land surface processes, and human inflows, outflows, and storage changes. Our current inability to adequately analyse and manage drought in many places points to gaps in our understanding and to inadequate data and tools. The Anthropocene requires a new framework for drought definitions and research. Drought definitions need to be revisited to explicitly include human processes driving and modifying soil moisture drought and hydrological drought development. We give recommendations for robust drought definitions to clarify timescales of drought and prevent confusion with related terms such as water scarcity and overexploitation. Additionally, our understanding and analysis of drought need to move from single driver to multiple drivers and from uni-directional to multi-directional. We identify research gaps and propose analysis approaches on (1) drivers, (2) modifiers, (3) impacts, (4) feedbacks, and (5) changing the baseline of drought in the Anthropocene. The most pressing research questions are related to the attribution of drought to its causes, to linking drought impacts to drought characteristics, and to societal adaptation and responses to drought. Example questions include (i) What are the dominant drivers of drought in different parts of the world? (ii) How do human modifications of drought enhance or alleviate drought severity? (iii) How do impacts of drought depend on the physical characteristics of drought vs. the vulnerability of people or the environment? (iv) To what extent are physical and human drought processes coupled, and can feedback loops be identified and altered to lessen or mitigate drought? (v) How should we adapt our drought analysis to accommodate changes in the normal situation (i.e. what are considered normal or reference conditions) over time? Answering these questions requires exploration of qualitative and quantitative data as well as mixed modelling approaches. The challenges related to drought research and management in the Anthropocene are not unique to drought, but do require urgent attention. We give recommendations drawn from the fields of flood research, ecology, water management, and water resources studies. The framework presented here provides a holistic view on drought in the Anthropocene, which will help improve management strategies for mitigating the severity and reducing the impacts of droughts in future.
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- Beck, Hylke E., et al.
(författare)
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Global Fully Distributed Parameter Regionalization Based on Observed Streamflow From 4,229 Headwater Catchments
- 2020
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Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 125:17
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Tidskriftsartikel (refereegranskat)abstract
- All hydrological models need to be calibrated to obtain satisfactory streamflow simulations. Here we present a novel parameter regionalization approach that involves the optimization of transfer equations linking model parameters to climate and landscape characteristics. The optimization was performed in a fully spatially distributed fashion at high resolution (0.05 degrees), instead of at lumped catchment scale, using an unprecedented database of daily observed streamflow from 4,229 headwater catchments (<5,000 km(2)) worldwide. The optimized equations were subsequently applied globally to produce parameter maps for the entire land surface including ungauged regions. The approach was evaluated using the Kling-Gupta efficiency (KGE) and a gridded version of the hydrological model HBV. Tenfold cross validation was used to evaluate the generalizability of the approach and to obtain an ensemble of parameter maps. For the 4,229 independent validation catchments, the regionalized parameters yielded a median KGE of 0.46. The median KGE improvement (relative to uncalibrated parameters) was 0.29, and improvements were obtained for 88% of the independent validation catchments. These scores compare favorably to those from previous large catchment sample studies. The degree of performance improvement due to the regionalized parameters did not depend on climate or topography. Substantial improvements were obtained even for independent validation catchments located far from the catchments used for optimization, underscoring the value of the derived parameters for poorly gauged regions. The regionalized parameters-available via -should be useful for hydrological applications requiring accurate streamflow simulations.
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