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Sökning: WFRF:(Morley Christopher P)

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  • Arking, Dan E, et al. (författare)
  • Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
  • 2014
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
  • Tidskriftsartikel (refereegranskat)abstract
    • The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
  • Roselli, Carolina, et al. (författare)
  • Multi-ethnic genome-wide association study for atrial fibrillation
  • 2018
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
  • 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.
  • Gardiner, Nicholas J., et al. (författare)
  • The crustal architecture of Myanmar imaged through zircon U-Pb, Lu-Hf and O isotopes : Tectonic and metallogenic implications
  • 2018
  • Ingår i: Gondwana Research. - 1342-937X. ; 62, s. 27-60
  • Tidskriftsartikel (refereegranskat)abstract
    • The Tethys margin in central and eastern Asia is comprised of continental terranesseparated by suture zones, some of which remain cryptic. Determining the crustal architecture, and therefore the geological history, of the Eastern Tethyan margin remains challenging. Sited in the heart of this region, Myanmar is a highly prospective but poorly explored minerals jurisdiction. A better understanding of Myanmar's mineralization can only be realized through a better understanding of its tectonic history, itself reflected in at least four major magmatic belts. The Eastern and the Main Range Provinces are associated with the Late Permian to Early Triassic closure of Palaeo-Tethys. The Mogok–Mandalay–Mergui Belt and Wuntho–Popa Arc are a response to the Eocene closure of Neo-Tethys. However, magmatic ages outside these two orogenic events are also recorded. We present new zirconU-Pb, Lu-Hf and O isotope data from magmatic rocks across Myanmar, which we append to the existing dataset to isotopically characterize Myanmar's magmatic belts. Eastern Province Permian I-type magmatism has evolved εHf (−10.9 to −6.4), whilst Main Range Province Triassic S-type magmatism also records evolved εHf (−13.5 to −8.8). The Mogok-Mandalay-Mergui Belt is here divided into the Tin Province and the Mogok Metamorphic Belt. The Tin Province hosts ca. 77–50 Ma magmatism with evolved εHf (−1.2 to −15.2), and δ18O of 5.6–8.3‰. The Mogok Metamorphic Belt exhibits a more complex magmatic and metamorphic history, and granitoids record Jurassic, Late Cretaceous, and Eocene to Miocene phases of magmatism, all of which exhibit evolved εHf values between −4.6 and −17.6, and δ18O between 6.3 and 9.2‰. From the Tagaung-Myitkyina Belt, we report a magmatic age of 172 Ma and εHf of 18.1 to 10.8. To accommodate the geological evidence, we propose a tectonic model for Myanmar involving a greater Sibumasu – where the documented zircon isotopic variations reflect compositional variations in magmatic source – and invoke the role of a Tengchong Block. The Baoshan Block and Greater Sibumasu were likely assembled on or before the Triassic, a former Andean margin and suture which may lie across the Northern Shan Plateau, and reflected in isotopic differences between the northern and southern parts of the Mogok Metamorphic Belt. This contiguous Sibumasu–Baoshan Block then sutured onto the Indochina margin in the Late Triassic. We propose that a Tengchong Block within Myanmar provides for a southerly termination of the Meso-Tethys suture immediately north of the Mogok area. A discrete Tengchong Block may explain a discontinuous arc of Late Triassic to Jurassic I-type magmatism in central Myanmar, representing an Andean-type margin sited above a subducting Meso-Tethys on the margin of Sibumasu. The Tengchong Block sutured onto Greater Sibumasu before the Late Cretaceous, after which subduction of Neo-Tethys drove the magmatism of the Wuntho-Popa Arc and ultimately that of the Tin Province. The metallogenic character of granite belts in Myanmar reflects the crustal architecture of the region, which is remarkable for its prolific endowment of granite-hosted Sn-W mineralization in two quite distinct granite belts related to sequential Indosinian and Himalayan orogenesis.
  • Charney, Alexander W, et al. (författare)
  • Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.
  • 2019
  • Ingår i: Biological psychiatry. - 1873-2402. ; 86:2, s. 110-119
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
  • Smith, Gustav, et al. (författare)
  • Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
  • 2016
  • Ingår i: PLoS Genetics. - Public Library of Science. - 1553-7390. ; 12:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
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