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- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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- Ashizawa, T., et al.
(författare)
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Consensus-based care recommendations for adults with myotonic dystrophy type 1
- 2018
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Ingår i: Neurology-Clinical Practice. - : Ovid Technologies (Wolters Kluwer Health). - 2163-0402 .- 2163-0933. ; 8:6, s. 507-520
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Forskningsöversikt (refereegranskat)abstract
- Purpose of review Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.
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- Liu, E. J., et al.
(författare)
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Aerial strategies advance volcanic gas measurements at inaccessible, strongly degassing volcanoes
- 2020
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:44
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Tidskriftsartikel (refereegranskat)abstract
- Volcanic emissions are a critical pathway in Earth's carbon cycle. Here, we show that aerial measurements of volcanic gases using unoccupied aerial systems (UAS) transform our ability to measure and monitor plumes remotely and to constrain global volatile fluxes from volcanoes. Combining multi-scale measurements from ground-based remote sensing, long-range aerial sampling, and satellites, we present comprehensive gas fluxes-3760 ± [600, 310] tons day-1 CO2 and 5150 ± [730, 340] tons day-1 SO2-for a strong yet previously uncharacterized volcanic emitter: Manam, Papua New Guinea. The CO2/ST ratio of 1.07 ± 0.06 suggests a modest slab sediment contribution to the sub-arc mantle. We find that aerial strategies reduce uncertainties associated with ground-based remote sensing of SO2 flux and enable near-real-time measurements of plume chemistry and carbon isotope composition. Our data emphasize the need to account for time averaging of temporal variability in volcanic gas emissions in global flux estimates.
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- Legius, E., et al.
(författare)
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Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation
- 2021
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 23, s. 1506-1513
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Tidskriftsartikel (refereegranskat)abstract
- Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.
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- Galle, Bo, 1952, et al.
(författare)
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A multi-purpose, multi-rotor drone system for long-range and high-altitude volcanic gas plume measurements
- 2021
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Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 14:6, s. 4255-4277
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Tidskriftsartikel (refereegranskat)abstract
- A multi-rotor drone has been adapted for studies of volcanic gas plumes. This adaptation includes improved capacity for high-altitude and long-range, real-time SO2 concentration monitoring, long-range manual control, remotely activated bag sampling and plume speed measurement capability. The drone is capable of acting as a stable platform for various instrument configurations, including multi-component gas analysis system (MultiGAS) instruments for in situ measurements of SO2, H2S, and CO2 concentrations in the gas plume and portable differential optical absorption spectrometer (MobileDOAS) instruments for spectroscopic measurement of total SO2 emission rate, remotely controlled gas sampling in bags and sampling with gas denuders for posterior analysis on the ground of isotopic composition and halogens. The platform we present was field-tested during three campaigns in Papua New Guinea: in 2016 at Tavurvur, Bagana and Ulawun volcanoes, in 2018 at Tavurvur and Langila volcanoes and in 2019 at Tavurvur and Manam volcanoes, as well as in Mt. Etna in Italy in 2017. This paper describes the drone platform and the multiple payloads, the various measurement strategies and an algorithm to correct for different response times of MultiGAS sensors. Specifically, we emphasize the need for an adaptive flight path, together with live data transmission of a plume tracer (such as SO2 concentration) to the ground station, to ensure optimal plume interception when operating beyond the visual line of sight. We present results from a comprehensive plume characterization obtained during a field deployment at Manam volcano in May 2019. The Papua New Guinea region, and particularly Manam volcano, has not been extensively studied for volcanic gases due to its remote location, inaccessible summit region and high level of volcanic activity. We demonstrate that the combination of a multi-rotor drone with modular payloads is a versatile solution to obtain the flux and composition of volcanic plumes, even for the case of a highly active volcano with a high-altitude plume such as Manam. Drone-based measurements offer a valuable solution to volcano research and monitoring applications and provide an alternativespan idCombining double low line"page4256"/> and complementary method to ground-based and direct sampling of volcanic gases.
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- Shah, S, et al.
(författare)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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- Wray, Selina, et al.
(författare)
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Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
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