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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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- 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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- 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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- McMahon, J J, et al.
(författare)
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CMP compatibility of partially cured benzocyclobutene (BCB) for a via-first 3D IC process
- 2005
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Ingår i: Chemical-Mechanical Planarization-Integration, Technology and Reliability. - WARRENDALE, PA : MATERIALS RESEARCH SOCIETY. - 1558998209 ; , s. 63-68
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Konferensbidrag (refereegranskat)abstract
- Wafer-level three dimensional (3D) IC technology offers the promise of decreasing RC delays by reducing long interconnect lines in high performance ICs. This paper focuses on a via-first 3D IC platform, which utilizes a back-end-of-line (BEOL) compatible damascene-patterned layer of copper and Benzocyclobutene (BCB). This damascene-patterned copper/BCB serves as a redistribution layer between two fully fabricated wafer sets of ICs and offers the potential of high bonding strength and low contact resistance for inter-wafer interconnects between the wafer pair. The process would thus combine the electrical advantages of 3D technology using Cu-to-Cu bonding with the mechanical advantages of 3D technology using BCB-to-BCB bonding. In this work, partially cured BCB has been evaluated for copper damascene patterning using commercially available CMP slurries as a key process step for a via-first 3D process flow. BCB is spin-cast on 200 mm wafers and cured at temperatures ranging from 190 degrees C to 250 degrees C, providing a wide range of crosslink percentage. These films are evaluated for CMP removal rate, surface damage (surface scratching and embedded abrasives), and planarity with commercially available copper CMP slurries. Under baseline process parameters, erosion, and roughness changes are presented for single-level damascene test patterns. After wafers are bonded under controlled temperature and pressure, the bonding interface is inspected optically using glass-to-silicon bonded wafers, and the bond strength is evaluated by a razor blade test.
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