| 1. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 2. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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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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| 3. |
- Jallow, Muminatou, et al.
(författare)
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Genome-wide and fine-resolution association analysis of malaria in West Africa.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 657-665
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
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| 4. |
- Meier, H. E. Markus, et al.
(författare)
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Ensemble Modeling of the Baltic Sea Ecosystem to Provide Scenarios for Management
- 2014
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 43:1, s. 37-48
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Tidskriftsartikel (refereegranskat)abstract
- We present a multi-model ensemble study for the Baltic Sea, and investigate the combined impact of changing climate, external nutrient supply, and fisheries on the marine ecosystem. The applied regional climate system model contains state-of-the-art component models for the atmosphere, sea ice, ocean, land surface, terrestrial and marine biogeochemistry, and marine food-web. Time-dependent scenario simulations for the period 1960-2100 are performed and uncertainties of future projections are estimated. In addition, reconstructions since 1850 are carried out to evaluate the models sensitivity to external stressors on long time scales. Information from scenario simulations are used to support decision-makers and stakeholders and to raise awareness of climate change, environmental problems, and possible abatement strategies among the general public using geovisualization. It is concluded that the study results are relevant for the Baltic Sea Action Plan of the Helsinki Commission.
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| 5. |
- Meier, Markus, et al.
(författare)
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Comparing reconstructed past variations and future projections of the Baltic sea ecosystem first results from multi model ensemble simulations
- 2012
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 7:3, s. 034005-
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Tidskriftsartikel (refereegranskat)abstract
- Multi-model ensemble simulations for the marine biogeochemistry and food web of the Baltic Sea were performed for the period 1850-2098, and projected changes in the future climate were compared with the past climate environment. For the past period 1850-2006, atmospheric, hydrological and nutrient forcings were reconstructed, based on historical measurements. For the future period 1961-2098, scenario simulations were driven by regionalized global general circulation model (GCM) data and forced by various future greenhouse gas emission and air-and riverborne nutrient load scenarios (ranging from a pessimistic 'business-as-usual' to the most optimistic case). To estimate uncertainties, different models for the various parts of the Earth system were applied. Assuming the IPCC greenhouse gas emission scenarios A1B or A2, we found that water temperatures at the end of this century may be higher and salinities and oxygen concentrations may be lower than ever measured since 1850. There is also a tendency of increased eutrophication in the future, depending on the nutrient load scenario. Although cod biomass is mainly controlled by fishing mortality, climate change together with eutrophication may result in a biomass decline during the latter part of this century, even when combined with lower fishing pressure. Despite considerable shortcomings of state-of-the-art models, this study suggests that the future Baltic Sea ecosystem may unprecedentedly change compared to the past 150 yr. As stakeholders today pay only little attention to adaptation and mitigation strategies, more information is needed to raise public awareness of the possible impacts of climate change on marine ecosystems.
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| 6. |
- Pausata, Francesco S. R., et al.
(författare)
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Tropical cyclone activity enhanced by Sahara greening and reduced dust emissions during the African Humid Period
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:24, s. 6221-6226
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Tidskriftsartikel (refereegranskat)abstract
- Tropical cyclones (TCs) can have devastating socioeconomic impacts. Understanding the nature and causes of their variability is of paramount importance for society. However, historical records of TCs are too short to fully characterize such changes and paleosediment archives of Holocene TC activity are temporally and geographically sparse. Thus, it is of interest to apply physical modeling to understanding TC variability under different climate conditions. Here we investigate global TC activity during a warm climate state (mid-Holocene, 6,000 yBP) characterized by increased boreal summer insolation, a vegetated Sahara, and reduced dust emissions. We analyze a set of sensitivity experiments in which not only solar insolation changes are varied but also vegetation and dust concentrations. Our results show that the greening of the Sahara and reduced dust loadings lead to more favorable conditions for tropical cyclone development compared with the orbital forcing alone. In particular, the strengthening of the West African Monsoon induced by the Sahara greening triggers a change in atmospheric circulation that affects the entire tropics. Furthermore, whereas previous studies suggest lower TC activity despite stronger summer insolation and warmer sea surface temperature in the Northern Hemisphere, accounting for the Sahara greening and reduced dust concentrations leads instead to an increase of TC activity in both hemispheres, particularly over the Caribbean basin and East Coast of North America. Our study highlights the importance of regional changes in land cover and dust concentrations in affecting the potential intensity and genesis of past TCs and suggests that both factors may have appreciable influence on TC activity in a future warmer climate.
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