| 1. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 2. |
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| 3. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 4. |
- Winkler, TW, et al.
(författare)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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| 5. |
- Young, William J., et al.
(författare)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Calderón-Contreras, Rafael, et al.
(författare)
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A regional PECS node built from place-based social-ecological sustainability research in Latin America and the Caribbean
- 2022
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Ingår i: Ecosystems and People. - : Informa UK Limited. - 2639-5908 .- 2639-5916. ; 18:1, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Sustainability requires a combination of meaningful co-production of locally relevant solutions, synthesis of insights gained across regions, and increased cooperation between science, policy and practice. The Programme for Ecosystem Change and Society (PECS) has been coordinating Place-Based Social-Ecological Sustainability Research (PBSESR) across the globe and emphasizes the need for regional scientific nodes from diverse biocultural regions to inform sustainability science and action. In this paper, we assess the strengths of the PBSESR communities in Latin America and the Caribbean (LAC). We provide an overview of PBSESR literature associated with this region and highlight the achievements of two prominent regional networks: The Social-Ecological Systems and Sustainability Research Network from Mexico (SocioEcoS) and the South American Institute for Resilience and Sustainability Studies from Uruguay (SARAS Institute). Finally, we identify the potential in these nodes to constitute a regional PECS node in Latin America and discuss the capacity needed to ensure such function. The results of the literature review show that while still loosely interconnected across the region, networks play key roles in connecting otherwise cloistered teams and we illustrate how the SocioEcoS network (focusing on transdisciplinary co-production of knowledge towards sustainability) and the SARAS Institute (focusing on innovative approaches for looking at complex social-ecological problems, rooted in slow science and arts) operate as key connectors in the region. We conclude that these organizations combined can embody a Latin American node for PECS, and would thereby not only contribute to regional but also global capacities to advance the sustainability agenda.
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| 7. |
- Wang, Mingyi, et al.
(författare)
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Synergistic HNO3–H2SO4–NH3 upper tropospheric particle formation
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 605:7910, s. 483-489
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Tidskriftsartikel (refereegranskat)abstract
- New particle formation in the upper free troposphere is a major global source of cloud condensation nuclei (CCN). However, the precursor vapours that drive the process are not well understood. With experiments performed under upper tropospheric conditions in the CERN CLOUD chamber, we show that nitric acid, sulfuric acid and ammonia form particles synergistically, at rates that are orders of magnitude faster than those from any two of the three components. The importance of this mechanism depends on the availability of ammonia, which was previously thought to be efficiently scavenged by cloud droplets during convection. However, surprisingly high concentrations of ammonia and ammonium nitrate have recently been observed in the upper troposphere over the Asian monsoon region. Once particles have formed, co-condensation of ammonia and abundant nitric acid alone is sufficient to drive rapid growth to CCN sizes with only trace sulfate. Moreover, our measurements show that these CCN are also highly efficient ice nucleating particles—comparable to desert dust. Our model simulations confirm that ammonia is efficiently convected aloft during the Asian monsoon, driving rapid, multi-acid HNO3–H2SO4–NH3 nucleation in the upper troposphere and producing ice nucleating particles that spread across the mid-latitude Northern Hemisphere.
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| 8. |
- Chapin III, F. Stuart, et al.
(författare)
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Earth stewardship : Shaping a sustainable future through interacting policy and norm shifts
- 2022
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 51:9, s. 1907-1920
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Tidskriftsartikel (refereegranskat)abstract
- Transformation toward a sustainable future requires an earth stewardship approach to shift society from its current goal of increasing material wealth to a vision of sustaining built, natural, human, and social capital—equitably distributed across society, within and among nations. Widespread concern about earth’s current trajectory and support for actions that would foster more sustainable pathways suggests potential social tipping points in public demand for an earth stewardship vision. Here, we draw on empirical studies and theory to show that movement toward a stewardship vision can be facilitated by changes in either policy incentives or social norms. Our novel contribution is to point out that both norms and incentives must change and can do so interactively. This can be facilitated through leverage points and complementarities across policy areas, based on values, system design, and agency. Potential catalysts include novel democratic institutions and engagement of non-governmental actors, such as businesses, civic leaders, and social movements as agents for redistribution of power. Because no single intervention will transform the world, a key challenge is to align actions to be synergistic, persistent, and scalable.
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| 9. |
- Levin, Simon A., et al.
(författare)
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Governance in the Face of Extreme Events : Lessons from Evolutionary Processes for Structuring Interventions, and the Need to Go Beyond
- 2022
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Ingår i: Ecosystems (New York. Print). - : Springer Science and Business Media LLC. - 1432-9840 .- 1435-0629. ; 25:3, s. 697-711
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Tidskriftsartikel (refereegranskat)abstract
- The increasing frequency of extreme events, exogenous and endogenous, poses challenges for our societies. The current pandemic is a case in point; but once-in-a-century weather events are also becoming more common, leading to erosion, wildfire and even volcanic events that change ecosystems and disturbance regimes, threaten the sustainability of our life-support systems, and challenge the robustness and resilience of societies. Dealing with extremes will require new approaches and large-scale collective action. Preemptive measures can increase general resilience, a first line of protection, while more specific reactive responses are developed. Preemptive measures also can minimize the negative effects of events that cannot be avoided. In this paper, we first explore approaches to prevention, mitigation and adaptation, drawing inspiration from how evolutionary challenges have made biological systems robust and resilient, and from the general theory of complex adaptive systems. We argue further that proactive steps that go beyond will be necessary to reduce unacceptable consequences.
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