| 1. |
- Schunkert, Heribert, et al.
(author)
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
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Journal article (peer-reviewed)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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| 2. |
- Voight, Benjamin F, et al.
(author)
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Plasma HDL cholesterol and risk of myocardial infarction : a mendelian randomisation study
- 2012
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 380:9841, s. 572-580
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Journal article (peer-reviewed)abstract
- BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
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| 3. |
- Settele, Josef, et al.
(author)
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Rice ecosystem services in South-east Asia
- 2018
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In: Paddy and Water Environment. - : Springer. - 1611-2490 .- 1611-2504. ; 16:2, s. 211-224
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Journal article (other academic/artistic)
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| 4. |
- Young, William J., et al.
(author)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Journal article (peer-reviewed)abstract
- The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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| 5. |
- Assimes, Themistocles L., et al.
(author)
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Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
- 2010
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 56:19, s. 1552-1563
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Journal article (peer-reviewed)abstract
- Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation
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| 6. |
- Tsoi, Lam C., et al.
(author)
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Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci
- 2015
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In: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 6:7001
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Journal article (peer-reviewed)abstract
- Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.
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| 7. |
- Haase, Peter, et al.
(author)
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Moderate warming over the past 25 years has already reorganized stream invertebrate communities
- 2019
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In: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 658, s. 1531-1538
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Journal article (peer-reviewed)abstract
- Climate warming often results in species range shifts, biodiversity loss and accumulated climatic debts of biota (i.e. slower changes in biota than in temperature). Here, we analyzed the changes in community composition and temperature signature of stream invertebrate communities over 25 years (1990-€“2014), based on a large set of samples (n = 3782) over large elevation, latitudinal and longitudinal gradients in central Europe. Although warming was moderate (average 0.5°C), we found a strong reorganization of stream invertebrate communities. Total abundance (+35.9%) and richness (+39.2%) significantly increased. The share of abundance (TA) and taxonomic richness (TR) of warm-dwelling taxa (TA: +73.2%; TR: +60.2%) and medium-temperature-dwelling taxa (TA: +0.4%; TR: +5.8%) increased too, while cold-dwelling taxa declined (TA: -61.5%; TR: -ˆ’47.3%). The community temperature index, representing the temperature signature of stream invertebrate communities, increased at a similar pace to physical temperature, indicating a thermophilization of the communities and, for the first time, no climatic debt. The strongest changes occurred along the altitudinal gradient, suggesting that stream invertebrates use the spatial configuration of river networks to track their temperature niche uphill. Yet, this may soon come to an end due to the summit trap effect. Our results indicate an ongoing process of replacement of cold-adapted species by thermophilic species at only 0.5 °C warming, which is particularly alarming in the light of the more drastic climate warming projected for coming decades.
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| 8. |
- Manfrin, Alessandro, et al.
(author)
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Taxonomic and functional reorganization in Central European stream macroinvertebrate communities over 25 years
- 2023
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In: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 889
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Journal article (peer-reviewed)abstract
- Climate warming can lead to a replacement of species that favour cold temperatures by species that favour warm temperatures. However, the implications of such thermic shifts for the functioning of ecosystems remain poorly understood. Here, we used stream macroinvertebrate biological and ecological traits to quantify the relative contribution of cold, intermediate and warm temperature-adapted taxa to changes in community functional diversity (FD) using a dataset of 3781 samples collected in Central Europe over 25 years, from 1990 to 2014.Our analyses indicated that functional diversity of stream macroinvertebrate communities increased over the study period. This gain was driven by a net 39 % increase in the richness of taxa that favour intermediate temperatures, which comprise the highest share in the community, and to a 97 % increase in the richness of taxa that favour warm temperatures. These warm temperature-adapted taxa displayed a distinct and more diverse suite of functional traits compared to the cold temperature-adapted group and thus contributed disproportionately to local FD on a per-taxon basis. At the same time, taxonomic beta-diversity declined significantly within each thermal group, in association with increasing local taxon richness.This study shows that over recent decades, small low-mountain streams in Central Europe have experienced a process of thermophilization and increasing functional diversity at local scales. However, a progressive homogenisation occurred at the regional scale, with communities converging towards similar taxonomic composition. As the reported increase in local functional diversity can be attributed mostly to the intermediate temperature-adapted taxa and a few expanding warm temperature-adapted taxa, these patterns could mask more subtle loss of sensitive cold temperature-adapted taxa with irreplaceable functional traits. In light of increasing climate warming, preservation of cold habitat refuges, should be considered a priority in river conservation.
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| 9. |
- Pilotto, Francesca, et al.
(author)
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Diverging response patterns of terrestrial and aquatic species to hydromorphological restoration
- 2019
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In: Conservation Biology. - : John Wiley & Sons. - 0888-8892 .- 1523-1739. ; 33:1, s. 132-141
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Journal article (peer-reviewed)abstract
- Although experiences with ecological restoration continue to accumulate, the effectiveness of restoration for biota remains debated. We complemented a traditional taxonomic analysis approach with information on 56 species traits to uncover the responses of 3 aquatic (fish, macroinvertebrates, macrophytes) and 2 terrestrial (carabid beetles, floodplain vegetation) biotic groups to 43 hydromorphological river restoration projects in Germany. All taxonomic groups responded positively to restoration, as shown by increased taxonomic richness (10–164%) and trait diversity (habitat, dispersal and mobility, size, form, life history, and feeding groups) (15–120%). Responses, however, were stronger for terrestrial than aquatic biota, and, contrary to our expectation, taxonomic responses were stronger than those of traits. Nevertheless, trait analysis provided mechanistic insights into the drivers of community change following restoration. Trait analysis for terrestrial biota indicated restoration success was likely enhanced by lateral connectivity and reestablishment of dynamic processes in the floodplain. The weaker response of aquatic biota suggests recovery was hindered by the persistence of stressors in the aquatic environment, such as degraded water quality, dispersal constraints, and insufficient hydromorphological change. Therefore, river restoration requires combined local- and regional-scale approaches to maximize the response of both aquatic and terrestrial organisms. Due to the contrasting responses of aquatic and terrestrial biota, the planning and assessment of river restoration outcomes should consider effects on both components of riverine landscapes.
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