Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - http://www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.

Research in Progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK)

The UK Refractory Asthma Stratification Programme(RASP-UK) will explore novel biomarker stratificationstrategies in severe asthma to improve clinicalmanagement and accelerate development of newtherapies. Prior asthma mechanistic studies have notstratified on inflammatory phenotype and theunderstanding of pathophysiological mechanisms inasthma without Type 2 cytokine inflammation is limited.RASP-UK will objectively assess adherence tocorticosteroids (CS) and examine a novel compositebiomarker strategy to optimise CS dose; this will alsoaddress what proportion of patients with severe asthmahave persistent symptoms without eosinophilic airwaysinflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.

Myeloproliferative neoplasm patient symptom burden and quality of life: evidence of significant impairment compared to controls

The myeloproliferative neoplasms (MPN) including polycythaemia vera (PV), essential thrombocythaemia and primary myelofibrosis (PMF) are rare diseases contributing to significant morbidity. Symptom management is a prime treatment objective but current symptom assessment tools have not been validated compared to the general population. The MPN-symptom assessment form (MPN-SAF), a reliable and validated clinical tool to assess MPN symptom burden, was administered to MPN patients (n = 106) and, for the first time, population controls (n = 124) as part of a UK case–control study. Mean symptom scores were compared between patients and controls adjusting for potential confounders. Mean patient scores were compared to data collected by the Mayo Clinic, USA on 1,446 international MPN patients to determine patient group representativeness. MPN patients had significantly higher mean scores than controls for 25 of the 26 symptoms measured (P < 0.05); fatigue was the most common symptom (92.4% and 78.1%, respectively). Female MPN patients suffered worse symptom burden than male patients (P < 0.001) and substantially worse burden than female controls (P < 0.001). Compared to the Mayo clinic patients, MPN-UK patients reported similar symptom burden but lower satiety (P = 0.046). Patients with PMF reported the worst symptom burden (88.3%); significantly higher than PV patients (P < 0.001). For the first time we report quality of life was worse in MPN-UK patients compared with controls (P < 0.001).

Accumulation of the PX domain mutant Frank-ter Haar syndrome protein Tks4 in aggresomes

BACKGROUND: Cells deploy quality control mechanisms to remove damaged or misfolded proteins. Recently, we have reported that a mutation (R43W) in the Frank-ter Haar syndrome protein Tks4 resulted in aberrant intracellular localization.

RESULTS: Here we demonstrate that the accumulation of Tks4(R43W) depends on the intact microtubule network. Detergent-insoluble Tks4 mutant colocalizes with the centrosome and its aggregate is encaged by the intermediate filament protein vimentin. Both the microtubule inhibitor nocodazole and the histone deacetylase inhibitor Trichostatin A inhibit markedly the aggresome formation in cells expressing Tks4(R43W). Finally, pretreatment of cells with the proteasome inhibitor MG132 markedly increases the level of aggresomes formed by Tks4(R43W). Furthermore, two additional mutant Tks4 proteins (Tks4(1-48) or Tks4(1-341)) have been investigated. Whereas the shorter Tks4 mutant, Tks4(1-48), shows no expression at all, the longer Tks4 truncation mutant accumulates in the nuclei of the cells.

CONCLUSIONS: Our results suggest that misfolded Frank-ter Haar syndrome protein Tks4(R43W) is transported via the microtubule system to the aggresomes. Lack of expression of Tks4(1-48) or aberrant intracellular expressions of Tks4(R43W) and Tks4(1-341) strongly suggest that these mutations result in dysfunctional proteins which are not capable of operating properly, leading to the development of FTHS.

Calvinist Absolutism: Archbishop James Ussher and Royal Power

Archbishop James Ussher's manuscript notebooks allow us to observe the making of a Calvinist absolutist and to orientate the archbishop's beliefs about royal power within European Reformed thought as a whole. By 1643, Ussher was preaching a polished and complete theory of absolute royal power, and it is possible to track the development of this political theory forward from his undergraduate days in the 1590s. Throughout his life Ussher engaged anxiously with Reformed theologians abroad, who generally favored limited rather than absolute monarchy. Nevertheless, Ussher shared with these Reformed colleagues both an antipathy to aspects of Aristotelian politics and a commitment to the divine institution of royal power. Finally, despite Ussher's hostility to Laudian innovations in the Irish Church, his heartfelt political beliefs made him a firm supporter of Stuart absolutism throughout the Three Kingdoms.

Essays on James Clarence Mangan: The Man in the Cloak

This volume explores the extraordinary literary achievement of James Clarence Mangan (1803-1849), increasingly recognised as one of the most important Irish writers of the nineteenth century and a crucial influence on later writers such as W.B. Yeats and James Joyce. It is the first collection of essays to focus on Mangan, and features articles by leading scholars in the field (including Jacques Chuto and David Lloyd) as well as contributions from acclaimed contemporary writers, Paul Muldoon and Ciaran Carson. The collection expands existing fields of debate--translation, the supernatural, intertextuality, nationalism, romanticism-- and introduces new ones: Mangan's afterlife in the English literary canon, cosmopolitanism and Weltliteratur, antiquity and futurity, nineteenth-century spiritualism and magical thinking. 'The man in the cloak', one of Mangan's favourite pseudonyms, is still a a resonant soubriquet for a writer who has eluded sustained critical attention, and this volumes restores him to his proper place in European and British, as well as Irish literary history.

‘Twenty-six things at once’: Pragmatic perspectives on Frank O’Hara and Norman Bluhm’s Poem-Paintings

Created over a couple of Sunday mornings in the Fall of 1960, the twenty-six collaborative Poem-Paintings of the artist Norman Bluhm and the poet Frank O'Hara represent what Bluhm later called a spontaneous 'conversation' between the painter and the poet. In this essay, Catherine Gander adopts a number of pragmatist positions to reconsider these overlooked works as essential examples of verbal-visual interaction that extend their 'conversation' to greet and involve us in a relationship that is at once interpersonal, integrated, and embodied. The works, Gander argues, constitute what John Dewey terms 'art as experience'; in their back and forth exchange of verbal and visual gesture, abstraction and denotation, the Poem-Paintings are the 'cumulative continuity' of 'the process of living', dramatising the shifting, spontaneous and multiple dimensions of interpersonal conversation, and in so doing, indicating a new path toward interconnective and equal exchange between word and image.

Max Weber and the First World War: Protestant and Catholic living standards in Germany, 1915-1919

We assess informal institutions of Protestants and Catholics by investigating their economic
resilience in a natural experiment. The First World War constitutes an exogenous shock to living standards since the duration and intensity of the war exceeded all expectations. We assess the ability of Protestant and Catholic communities to cope with increasing food prices and wartime black markets. Literature based on Weber (1904, 1905) suggests that Protestants must be more resilient than their Catholic peers. Using individual height data on some 2,800 Germans to assess levels of malnutrition during the war, we find that living standards for both Protestants and Catholics declined; however, the decrease of Catholics’ height was disproportionately large. Our empirical analysis finds a large statistically significant difference between Protestants and Catholics for the 1914-19 birth cohort, and we argue that this height gap cannot be attributed to socioeconomic background and fertility alone.

Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility

Small bowel accounts for only 0.5% of cancer cases in the US but incidence rates have been rising at 2.4% per year over the past decade. One-third of these are adenocarcinomas but little is known about their molecular pathology and no molecular markers are available for clinical use. Using a retrospective 28 patient matched normal-tumor cohort, next-generation sequencing, gene expression arrays and CpG methylation arrays were used for molecular profiling. Next-generation sequencing identified novel mutations in IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p < 0.01). Merging gene expression and DNA methylation data revealed CHN2 as consistently hypermethylated and downregulated in this disease (Spearman -0.71, p < 0.001). Mutations in TP53 which were found in more than half of the cohort (15/28) and Kazald1 hypomethylation were both were indicative of poor survival (p = 0.03, HR = 3.2 and p = 0.01, HR = 4.9 respectively). By integrating high-throughput mutational, gene expression and DNA methylation data, this study reveals for the first time the distinct molecular profile of small bowel adenocarcinoma and highlights potential clinically exploitable markers.

Truth at 24 frames a second? A working dialogue between a film-maker and a historical consultant about the making of The Enigma of Frank Ryan

We employ a practice-based methodology based on a ‘live’ film project to explore the different ways that film-makers and historians narrate the past. Through a case-study of the production and exhibition of a drama-documentary feature-film, The Enigma of Frank Ryan, on which both authors (film-maker Bell and historian McGarry) worked respectively as director and historical consultant, we explore a range of critical issues arising from our collaboration. Through a dialogue between a director and a historian, a model of good practice between historians and film-makers emerges.

The relationship between time attitudes profiles and self-efficacy, sensation seeking, and alcohol use: An exploratory study

A growing body of research has begun to report on time attitudes which specifically refers to an individual's emotional and evaluative feelings toward the past, the present, and the future. The present study used data from the first wave of a longitudinal cohort study in the United Kingdom. Sample 1 consisted of 1580 adolescents (40% female, 1.7% unreported) in Northern Ireland, while Sample 2 consisted of 813 adolescents (46.7% female, 1.4% unreported) in Scotland. Five similar time attitudes profiles emerged in both countries, with one additional "balanced" profile in Scotland. Results show that there were no substantive differences between profiles in terms of socio-demographic indicators. However, in respect of academic, social and emotional self-efficacy, best results were observed for those with Positive, Ambivalent, and Balanced profiles, with the reverse true for those with Negative, Past Negative, and Pessimistic profiles. Positives were also less likely to report using alcohol.

The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts

Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.