The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

Report of the workshop for life detection in samples from Mars

The question of whether there is or was life on Mars has been one of the most pivotal since Schiaparellis' telescopic observations of the red planet. With the advent of the space age, this question can be addressed directly by exploring the surface of Mars and by bringing samples to Earth for analysis. The latter, however, is not free of problems. Life can be found virtually everywhere on Earth. Hence the potential for contaminating the Mars samples and compromising their scientific integrity is not negligible. Conversely, if life is present in samples from Mars, this may represent a potential source of extraterrestrial biological contamination for Earth. A range of measures and policies, collectively termed ‘planetary protection’, are employed to minimise risks and thereby prevent undesirable consequences for the terrestrial biosphere. This report documents discussions and conclusions from a workshop held in 2012, which followed a public conference focused on current capabilities for performing life-detection studies on Mars samples. The workshop focused on the evaluation of Mars samples that would maximise scientific productivity and inform decision making in the context of planetary protection. Workshop participants developed a strong consensus that the same measurements could be employed to effectively inform both science and planetary protection, when applied in the context of two competing hypotheses: 1) that there is no detectable life in the samples; or 2) that there is martian life in the samples. Participants then outlined a sequence for sample processing and defined analytical methods that would test these hypotheses. They also identified critical developments to enable the analysis of samples from Mars.

Estimating the incidence, prevalence and true cost of asthma in the UK: Secondary analysis of national stand-alone and linked databases in England, Northern Ireland, Scotland and Wales-a study protocol

Introduction Asthma is now one of the most common long-term conditions in the UK. It is therefore important to develop a comprehensive appreciation of the healthcare and societal costs in order to inform decisions on care provision and planning. We plan to build on our earlier estimates of national prevalence and costs from asthma by filling the data gaps previously identified in relation to healthcare and broadening the field of enquiry to include societal costs. This work will provide the first UK-wide estimates of the costs of asthma. In the context of asthma for the UK and its member countries (ie, England, Northern Ireland, Scotland and Wales), we seek to: (1) produce a detailed overview of estimates of incidence, prevalence and healthcare utilisation; (2) estimate health and societal costs; (3) identify any remaining information gaps and explore the feasibility of filling these and (4) provide insights into future research that has the potential to inform changes in policy leading to the provision of more cost-effective care.

Methods and analysis Secondary analyses of data from national health surveys, primary care, prescribing, emergency care, hospital, mortality and administrative data sources will be undertaken to estimate prevalence, healthcare utilisation and outcomes from asthma. Data linkages and economic modelling will be undertaken in an attempt to populate data gaps and estimate costs. Separate prevalence and cost estimates will be calculated for each of the UK-member countries and these will then be aggregated to generate UK-wide estimates.

Ethics and dissemination Approvals have been obtained from the NHS Scotland Information Services Division's Privacy Advisory Committee, the Secure Anonymised Information Linkage Collaboration Review System, the NHS South-East Scotland Research Ethics Service and The University of Edinburgh's Centre for Population Health Sciences Research Ethics Committee. We will produce a report for Asthma-UK, submit papers to peer-reviewed journals and construct an interactive map.

The rise of the digital citizen-stakeholder: rebalancing multistakeholder governance

The principle feature in the evolution of the internet has been its ever growing reach to include old and young, rich and poor. The internet’s ever encroaching presence has transported it from our desktop to our pocket and into our glasses. This is illustrated in the Internet Society Questionnaire on Multistakeholder Governance, which found the main factors affecting change in the Internet governance landscape were more users online from more countries and the influence of the internet over daily life. The omnipresence of the internet is self- perpetuating; its usefulness grows with every new user and every new piece of data uploaded. The advent of social media and the creation of a virtual presence for each of us, even when we are not physically present or ‘logged on’, means we are fast approaching the point where we are all connected, to everyone else, all the time. We have moved far beyond the point where governments can claim to represent our views which evolve constantly rather than being measured in electoral cycles.
The shift, which has seen citizens as creators of content rather than consumers of it, has undermined the centralist view of democracy and created an environment of wiki democracy or crowd sourced democracy. This is at the heart of what is generally known as Web 2.0, and widely considered to be a positive, democratising force. However, we argue, there are worrying elements here too. Government does not always deliver on the promise of the networked society as it involves citizens and others in the process of government. Also a number of key internet companies have emerged as powerful intermediaries harnessing the efforts of the many, and re- using and re-selling the products and data of content providers in the Web 2.0 environment. A discourse about openness and transparency has been offered as a democratising rationale but much of this masks an uneven relationship where the value of online activity flows not to the creators of content but to those who own the channels of communication and the metadata that they produce.
In this context the state is just one stakeholder in the mix of influencers and opinion formers impacting on our behaviours, and indeed our ideas of what is public. The question of what it means to create or own something, and how all these new relationships to be ordered and governed are subject to fundamental change. While government can often appear slow, unwieldy and even irrelevant in much of this context, there remains a need for some sort of political control to deal with the challenges that technology creates but cannot by itself control. In order for the internet to continue to evolve successfully both technically and socially it is critical that the multistakeholder nature of internet governance be understood and acknowledged, and perhaps to an extent, re- balanced. Stakeholders can no longer be classified in the broad headings of government, private sector and civil society, and their roles seen as some sort of benign and open co-production. Each user of the internet has a stake in its efficacy and each by their presence and participation is contributing to the experience, positive or negative of other users as well as to the commercial success or otherwise of various online service providers. However stakeholders have neither an equal role nor an equal share. The unequal relationship between the providers of content and those who simple package up and transmit that content - while harvesting the valuable data thus produced - needs to be addressed. Arguably this suggests a role for government that involves it moving beyond simply celebrating and facilitating the on- going technological revolution. This paper reviews the shifting landscape of stakeholders and their contribution to the efficacy of the internet. It will look to critically evaluate the primacy of the individual as the key stakeholder and their supposed developing empowerment within the ever growing sea of data. It also looks at the role of individuals in wider governance roles. Governments in a number of jurisdictions have sought to engage, consult or empower citizens through technology but in general these attempts have had little appeal. Citizens have been too busy engaging, consulting and empowering each other to pay much attention to what their governments are up to. George Orwell’s view of the future has not come to pass; in fact the internet has insured the opposite scenario has come to pass. There is no big brother but we are all looking over each other’s shoulder all the time, while at the same time a number of big corporations are capturing and selling all this collective endeavour back to us.

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.