Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The genomics of heart failure: design and rationale of the HERMES consortium

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 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.</p

The genomics of heart failure: design and rationale of the HERMES consortium

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 &lt; 5 × 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

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

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

Anglo-Scandinavian literature and the post-conquest period

This thesis concerns narratives about Anglo-Scandinavian contact and literary traditions of Scandinavian origin which circulated in England in the post-conquest period.  The argument of the thesis is that in the eleventh century, particularly during the reign of Cnut and his sons, literature was produced for a mixed Anglo-Danish audience which drew on shared cultural traditions, and that some elements of this largely oral literature can be traced in later English sources.  It is further argued that in certain parts of England, especially the East Midlands, an interest in Anglo-Scandinavian history continued for several centuries after the Viking Age and was manifested in the circulation of literary narratives dealing with Anglo-Scandinavian interaction, invasion and settlement.  The first chapter discusses some narratives about the reign of Cnut in later sources, including the Encomium Emmae Reginae, hagiographical texts by Goscelin and Osbern of Canterbury, and the Liber Eliensis; it is argued that they share certain thematic concerns with the literature known to have been produced at Cnut’s court.  The second chapter explores the literary reputation of the Danish Earl of Northumbria, Siward, and his son Waltheof in twelfth-century sources from the East Midlands and in thirteenth-century Norwegian and Icelandic histories.  The third chapter deals with an episode in the Middle English romance Guy of Warwick in which the hero helps to defeat a Danish invasion of England, and examines the romance’s references to a historical Danish right to rule in England.  The final chapter discusses the Middle English romance Havelok the Dane, and argues that the poet of Havelok, aware of the role of Danish settlement in the history of Lincolnshire, makes self-conscious use of stereotypes and literary tropes associated with Danes in order to offer an imaginative reconstruction of the history of Danish settlement in the area.This thesis is not currently available in ORA

The representation of land and landownership in medieval Icelandic texts

This thesis investigates the representation of land and landownership in medieval Icelandic texts. I shall demonstrate that there is scant homogeneity in this representation; the variation between different narratives is startling and unusual. I seek to categorise this variability by identifying the lack of a secure tradition surrounding land and landownership, and exploring the possibilities open to the saga author to use land practices and myths as literary devices or to glorify the past. I also examine variability caused by the differences in the realm of 'actual' experience. I shall explore a range of narratives, from stories of the initial settlement of Iceland, to issues of inheritance, to conveyance and to dispute over territory. The last chapter takes a flip-side view of landownership to consider the representation of the landless of family saga narrative. The texts which I shall examine are the Íslendingasögur, Landnádmabók and Íslendingabók. Throughout the thesis I also make reference to Grágás for illumination and comparison. In the first and second chapters I also include archaeological evidence for discussion.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Ráð Rétt Rúnar : reading the runes in Old English and Old Norse poetry

Responding to the common plea in medieval inscriptions to ráð rétt rúnar, to ‘interpret the runes correctly’, this thesis provides a series of contextual readings of the runic topos in Anglo-Saxon and Old Norse poetry. The first chapter looks at the use of runes in the Old English riddles, examining the connections between material riddles and certain strategies used in the Exeter Book, and suggesting that runes were associated with a self-referential and engaged form of reading. Chapter 2 seeks a rationale for the use of runic abbreviations in Old English manuscripts, and proposes a poetic association with unlocking and revealing, as represented in Bede’s story of Imma. Chapter 3 considers the use of runes for their ornamental value, using 'Solomon and Saturn I' and the rune poems as examples of texts which foreground the visual and material dimension of writing, whilst Chapter 4 compares the depiction of runes in the heroic poems of the Poetic Edda with epigraphical evidence from the Migration Age, seeking to dispel the idea that they reflect historical practice. The final chapter looks at the construction of a mythology of writing in the Edda, exploring the ways in which myth reflects the social impacts of literacy. Taken together these approaches highlight the importance of reading the runes in poetry as literary constructs, the script often functioning as a form of metawriting, used to explore the parameters of literacy, and to draw attention to the process of writing itself.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Beyond sorrow and swords: gender in the Old Norse Volsung legend and its British rewritings

This thesis explores male and female identity in Old Norse and British iterations of the V&ouml;lsung legend, focusing on the Poetic Edda and V&ouml;lsunga saga, William Morris's The Story of Sigurd the Volsung and the Fall of the Niblungs, J. R. R. Tolkien's The Legend of Sigurd and Gudr&uacute;n, and Melvin Burgess’s Bloodtide and Bloodsong. Using poststructuralist theories of gender and posthumanism to analyse representations of gender in these texts, it argues that, in the Old Norse versions of this legend, female identity is closely connected to the control of representations of narrative events, whereas male identity is subject to this control but becomes more overtly fluid in the depiction of shape-shifting. The thesis goes beyond previous critical analyses of gender in these texts which observe an active/ passive binary, or focus on female monstrosity and lament, and male heroism. Unlike most examinations of adaptations of this legend which focus on the medieval or Victorian material, this thesis provides a detailed exploration of The Story of Sigurd the Volsung and the Fall of the Niblungs in conjunction with its Old Norse sources. In doing so, it establishes the silencing of female characters by Morris's rewriting, and the foregrounding of male identity through a focus on the body, performance and the built environment. This thesis also considers both the Old Norse texts and Morris's poem alongside later, critically neglected, British versions of the legend to explore the ways in which narrative form influences the representation of the multiplicity of gender in The Legend of Sigurd and Gudr&uacute;n, and the importance of a posthuman conception of identity in Bloodtide and Bloodsong. The thesis argues that the Old Norse sources do not stand aside from their later interpretations as something complete and originary, but are themselves supplemented by the rewritings of Morris, Tolkien and Burgess; it is, therefore, necessary to foreground our knowledge of all these iterations of the narrative to offer a fuller understanding of gender in the Old Norse V&ouml;lsung legend and its British rewritings.This thesis is not currently available via ORA