| 1. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 2. |
- Daw, Tim M., et al.
(författare)
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Elasticity in ecosystem services : exploring the variable relationship between ecosystems and human well-being
- 2016
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Ingår i: Ecology and Society. - 1708-3087. ; 21:2
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Tidskriftsartikel (refereegranskat)abstract
- Although ecosystem services are increasingly recognized as benefits people obtain from nature, we still have a poor understanding of how they actually enhance multidimensional human well-being, and how well-being is affected by ecosystem change. We develop a concept of ecosystem service elasticity (ES elasticity) that describes the sensitivity of human well-being to changes in ecosystems. ES Elasticity is a result of complex social and ecological dynamics and is context dependent, individually variable, and likely to demonstrate nonlinear dynamics such as thresholds and hysteresis. We present a conceptual framework that unpacks the chain of causality from ecosystem stocks through flows, goods, value, and shares to contribute to the well-being of different people. This framework builds on previous conceptualizations, but places multidimensional well-being of different people as the final element. This ultimately disaggregated approach emphasizes how different people access benefits and how benefits match their needs or aspirations. Applying this framework to case studies of individual coastal ecosystem services in East Africa illustrates a wide range of social and ecological factors that can affect ES elasticity. For example, food web and habitat dynamics affect the sensitivity of different fisheries ecosystem services to ecological change. Meanwhile high cultural significance, or lack of alternatives enhance ES elasticity, while social mechanisms that prevent access can reduce elasticity. Mapping out how chains are interlinked illustrates how different types of value and the well-being of different people are linked to each other and to common ecological stocks. We suggest that examining chains for individual ecosystem services can suggest potential interventions aimed at poverty alleviation and sustainable ecosystems while mapping out of interlinkages between chains can help to identify possible ecosystem service trade-offs and winners and losers. We discuss conceptual and practical challenges of applying such a framework and conclude on its utility as a heuristic for structuring interdisciplinary analysis of ecosystem services and human well-being.
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| 3. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 4. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 5. |
- Van Hemelrijck, Mieke, et al.
(författare)
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Reasons for Discontinuing Active Surveillance : Assessment of 21 Centres in 12 Countries in the Movember GAP3 Consortium
- 2019
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 75:3, s. 523-531
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Tidskriftsartikel (refereegranskat)abstract
- Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa). Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation. Design, setting, and participants: We compared data from 10 296 men on AS from 21 centres across 12 countries. Outcome measurements and statistical analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation. Results and limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4–28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0–13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5–2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4–2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5 yr, 4561 had follow-up for <5 yr, and 149 were lost to follow-up. Cumulative incidence of progression was 27.5% (95% CI: 26.4–28.6%) at 5 yr and 38.2% (95% CI: 36.7–39.9%) at 10 yr. A limitation is that not all centres were included due to limited information on the reason for discontinuation and limited follow-up. Conclusions: Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression. Patient summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5 yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS.
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| 6. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Di Angelantonio, Emanuele, et al.
(författare)
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Major lipids, apolipoproteins, and risk of vascular disease
- 2009
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 302:18, s. 1993-2000
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified. OBJECTIVE: To assess major lipids and apolipoproteins in vascular risk. DESIGN, SETTING, AND PARTICIPANTS: Individual records were supplied on 302,430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes. MAIN OUTCOME MEASURES: Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 log(e) triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. RESULTS: The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non-HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non-HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C. CONCLUSION: Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.
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| 8. |
- Erdman, David, et al.
(författare)
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Parallel processing : Design/practice (servo)
- 2006
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Ingår i: Architectural Design. - : Wiley. - 0003-8504 .- 1554-2769. ; 76:5, s. 80-87
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Tidskriftsartikel (refereegranskat)abstract
- In the late 1990s servo emerged as a young design collaborative embracing new forms of distributed practice as enabled by the advent of telecommunications technologies. In this section, David Erdman, Marcelyn Gow, UIrika Karlsson and Chris Perry write about how these organisational principles are at work not only in the context of their practice, but in the design work itself, which stretches across a variety of design disciplines to incorporate areas of expertise particular to information and interaction design, as well as a number of manufacturing and fabrication technologies. Many of servo's projects have focused on small-scale interior infrastructures, typically in the form of gallery installations, furniture systems and exhibition designs. This particular scale has allowed the group to focus on the development of full-scale prototypes, exploring a wide range of potential innovations at the point of integration between various technological and material systems.
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| 9. |
- Gow, Marcelyn, et al.
(författare)
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Networks And Environments
- 2008
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Ingår i: Networks and environments. - Seoul : DAMDI Publishing Co.. - 9788991111349
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Bokkapitel (populärvet., debatt m.m.)abstract
- An architectural design collective, Servos focus is on the development of architectural environments, active design systems comprised of temporal conditions, the proliferation of electronic and digital equipment and interfaces, and in general the ebb and flow of information in real time. Recent projects include a full scale installation at the International Biennial of Contemporary Art in Seville and an exhibition design at the Santa Monica Museum of Art in Los Angeles. A total of thirteen works are presented here, illustrated by models, photographs and technical drawings, and accompanied by essays and experimental design research projects
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| 10. |
- Hammar, Linus, 1979, et al.
(författare)
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Cumulative impact assessment for ecosystem-based marine spatial planning
- 2020
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 734
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Tidskriftsartikel (refereegranskat)abstract
- Claims for ocean space are growing while marine ecosystems suffer from centuries of insufficient care. Human pressures from runoff, atmospheric emissions, marine pollution, fishing, shipping, military operations and other activities wear on habitats and populations. Ecosystem-based marine spatial planning (MSP) has emerged worldwide as a strategic instrument for handling conflicting spatial claims among competing sectors and the environment. The twofold objective of both boosting the blue economy and protecting the environment is challenging in practice and marine planners need decision support. Cumulative Impact Assessment (CIA) was originally developed to provide an overview of the human imprint on the world's ocean ecosystems. We have now added a scenario component to the CIA model and used it within Swedish ecosystem-based MSP. This has allowed us to project environmental impacts for different planning alternatives throughout the planning process, strengthening the integration of environmental considerations into strategic decision-making. Every MSP decision may entail a local shift of environmental impact, causing positive or negative consequences for ecosystem components. The results from Swedish MSP in the North Sea and Baltic Sea illustrate that MSP certainly has the potential to lower net cumulative environmental impact, both locally and across sea basins, as long as environmental values are rated high and prevailing pressures derive from activities that are part of MSP. By synthesizing innumerous data into comprehensible decision support that informs marine planners of the likely environmental consequences of different options, CIA enables ecosystem-based MSP in practice.
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