Discovering common genetic variants for hypertension using an extreme case-control strategy

Hypertension is a common, highly heritable trait of complex aetiology. Multiple environmental and lifestyle factors contribute to blood pressure variation. Hence the study of hypertension causality is not straightforward. Genetic linkage studies have implicated a number of loci involved in blood pressure regulation and the development of hypertension. Candidate gene association studies, however, have not reported any reproducible associations. Early genome-wide association studies (GWAS) showed remarkable success in identifying validated common variants associated with common diseases such as coronary artery disease and type 1 diabetes. However, the first GWAS of hypertension showed little success. This was largely because of a lack of statistical power and insufficient genomic coverage. Furthermore, it is widely believed that the failure of one GWAS of hypertension was partly due to misclassification of controls that were not phenotyped for blood pressure. Subsequently, two large international consortia-run GWAS of blood pressure as a quantitative trait produced tangible results. The current study is a GWAS of hypertension using an extreme case-control design. It employed intensive phenotyping and extreme case-control definitions to select a sample of individuals from a restricted geographical area of relative homogeneity. The aim was to reduce misclassification bias and increase the likelihood of detecting any genetic effects. Cases were sampled from the Nordic Diltiazem study, and defined as individuals younger than 60 years with at least two consecutive measurements of systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg. Controls were sampled from the prospective Malmö Diet and Cancer Study, and defined as individuals aged at least 50 years with SBP ≤ 120 mmHg and DBP ≤ 80 mmHg with no evidence of cardiovascular disease during ten years of follow-up. The groups represent, respectively, the upper 1.7% and lower 9.2% of the Swedish blood pressure distribution. Comparison of groups from the extreme tails of distribution increased statistical power by inflating observed effect sizes. With genome-wide SNP coverage we were able to adjust for population stratification using principal components analysis. Following quality control exclusions, a final set of 521,220 single nucleotide polymorphisms was available for analysis in 1,621 cases and 1,699 controls. Seventeen SNPs were associated with hypertension at a P < 1 × 10-5 threshold of significance, of which three attained genome-wide significance, defined as P < 5 × 10-7. The top hit, rs13333226, underwent a two stage validation process in a total of 14 independent cohorts. The combined odds ratio for the discovery cohort and all replication cohorts meta-analysed was 0.87 (95% CI 0.84 – 0.91, P = 3.67 × 10-11) with the minor G allele associated with a lower risk of hypertension. In total 21,466 cases and 18,240 controls were included. After adjustment for age, age2, sex, and BMI, and when the discovery cohort was excluded from analysis, the association remained significant. Estimated glomerular filtration rate (eGFR), a measure of kidney function, was available in seven of the cohorts. When the analysis was repeated with adjustment for eGFR the effect was marginally strengthened. rs13333226 is located in close proximity, at -1617 base pairs, to the uromodulin (UMOD) transcription start site. UMOD encodes uromodulin, also known as the Tamm-Horsfall protein. Uromodulin is produced predominantly in the thick ascending limb of the loop of Henle and is the most abundant protein in urine. Its function is unclear; however, variants in UMOD have been associated with chronic kidney disease. Clinical functional studies were conducted in three separate populations. The minor G allele of rs13333226 (associated with a lower risk of hypertension) was associated with lower urinary uromodulin excretion. Furthermore, in one sample following a low salt diet urinary uromodulin excretion was significantly lower in the presence of the G allele, whereas after a high salt diet genotype was no longer associated with urinary uromodulin. If this were verified, this would entail a gene-environment interaction. Our combined results suggest that UMOD may have a role in regulating blood pressure, possibly through an effect on sodium homeostasis. There is ample evidence of a strong, graded relationship between blood pressure and subsequent renal disease. Hence the current finding is biologically plausible. Information on kidney disease was not available for the discovery samples so this could not be explored. However, the association between rs13333226 and hypertension was not substantively altered by adjustment for eGFR in the seven validation cohorts in which it was recorded, suggesting that it is independent of renal function. In conclusion, we have performed a GWAS of hypertension using an extreme case-control design. The most significant hit was validated in a meta-analysis of the discovery sample and 14 additional cohorts. Moreover, functional studies showed a relationship between genotype and urinary protein excretion. Overall, we demonstrate that with careful methodological planning and phenotyping it is possible to generate replicable hypertension GWAS results in a relatively small sample size

Tunable narrow linewidth AlGaInP semiconductor disk laser for Sr atom cooling applications

We report a frequency stabilised semiconductor disk lasers based on AlGaInP and operating at 689 nm, a wavelength of interest for atomic clocks based on strontium atoms. With a gain structure designed for emission at around 690 nm, more than 100 mW of output power was generated in single frequency operation. We show that the source can be tuned over 8 nm with picometer precision. By servo-locking the frequency to the side of fringe of a reference cavity, we demonstrate rms frequency noise of 5.2 kHz

Tobacco Control Interest Groups and Their Influence on Parliamentary Committees in Canada

Objectives: The aim of this study was to determine how tobacco control interest groups influence tobacco policy decision-making through submissions and presentations to parliamentary committees. Methods: A qualitative content analysis was used to examine the presentations and submissions on tobacco-related legislation made to parliamentary committees between 1996 and 2004. The sample was identified from the public list of tobacco-related bills tabled in both the House of Commons and the Senate; the Government of Canada website and LEGISinfo were used to determine which committee reviewed the relevant bill. Committee clerks were asked to send submissions and presentations related to specific bills identified through LEGISinfo. Submissions and presentations were scanned and entered into QSR N6 software for coding. The coding instrument was adapted from previous studies employing qualitative content analysis. Montini and Bero\u27s recommendations were used to evaluate the submissions and presentations. Results: Tobacco control interest groups did present scientific evidence to support tobacco control. However, they underused credible witnesses to present information at meetings. The topics presented by tobacco control interests groups were usually relevant to the bill being discussed. Discussion: Tobacco control interest groups employed some of the strategies suggested by Montini and Bero in their attempt to influence parliamentary committees through submissions and presentations. They did include scientific evidence in their submissions; however, they could improve their strategies in the area of using credible witnesses, such as scientists and medical experts. Incorporating Montini and Bero\u27s recommendations into lobbying efforts may increase success in influencing committees

Detection of trend changes in time series using Bayesian inference

Change points in time series are perceived as isolated singularities where two regular trends of a given signal do not match. The detection of such transitions is of fundamental interest for the understanding of the system's internal dynamics. In practice observational noise makes it difficult to detect such change points in time series. In this work we elaborate a Bayesian method to estimate the location of the singularities and to produce some confidence intervals. We validate the ability and sensitivity of our inference method by estimating change points of synthetic data sets. As an application we use our algorithm to analyze the annual flow volume of the Nile River at Aswan from 1871 to 1970, where we confirm a well-established significant transition point within the time series.Comment: 9 pages, 12 figures, submitte

A Bayesian spatio-temporal model of panel design data: airborne particle number concentration in Brisbane, Australia

This paper outlines a methodology for semi-parametric spatio-temporal modelling of data which is dense in time but sparse in space, obtained from a split panel design, the most feasible approach to covering space and time with limited equipment. The data are hourly averaged particle number concentration (PNC) and were collected, as part of the Ultrafine Particles from Transport Emissions and Child Health (UPTECH) project. Two weeks of continuous measurements were taken at each of a number of government primary schools in the Brisbane Metropolitan Area. The monitoring equipment was taken to each school sequentially. The school data are augmented by data from long term monitoring stations at three locations in Brisbane, Australia. Fitting the model helps describe the spatial and temporal variability at a subset of the UPTECH schools and the long-term monitoring sites. The temporal variation is modelled hierarchically with penalised random walk terms, one common to all sites and a term accounting for the remaining temporal trend at each site. Parameter estimates and their uncertainty are computed in a computationally efficient approximate Bayesian inference environment, R-INLA. The temporal part of the model explains daily and weekly cycles in PNC at the schools, which can be used to estimate the exposure of school children to ultrafine particles (UFPs) emitted by vehicles. At each school and long-term monitoring site, peaks in PNC can be attributed to the morning and afternoon rush hour traffic and new particle formation events. The spatial component of the model describes the school to school variation in mean PNC at each school and within each school ground. It is shown how the spatial model can be expanded to identify spatial patterns at the city scale with the inclusion of more spatial locations.Comment: Draft of this paper presented at ISBA 2012 as poster, part of UPTECH projec

Genome-Wide Association Studies of Hypertension: Light at the End of the Tunnel

Despite its significant genetic component, the study of hypertension by genome-wide association presents more challenges than other common complex diseases. Its high prevalence, heterogeneity, and somewhat unclear definition are the challenges that need to be overcome on one hand. On the other hand, there are issues of small effect sizes and pleiotropism that are not specific to hypertension alone but nonetheless magnify the problems of genetic dissection when coupled with phenotypic misclassification. We discuss issues of study design and summarise published genome-wide association studies (GWASs) of hypertension and blood pressure. With careful study design and analysis success is possible, as demonstrated by the recent large-scale studies. Following these, there is still further scope to advance the field through high fidelity phenotyping and deep sequencing

Tunable, CW laser emission at 225 nm via intracavity frequency tripling in a semiconductor disk laser

Numerous applications would benefit from a compact laser source with tunable, continuous-wave emission in the deep ultraviolet (wavelengths <250nm); however, very few laser sources have been demonstrated with direct emission in this spectral region and options are generally limited to pulsed, fixed wavelength sources or complex and impractical setups for nonlinear frequency mixing of the emission of several infrared lasers in various external enhancement cavities. Here we propose an all-solid-state, continuous-wave, tunable laser with emission between 224 nm and 226 nm via intracavity frequency tripling in an AlGaInP-based semiconductor disk laser (SDL). Output power up to 78 µW is achieved in CW operation, with a tuning range over 350 cm-1. AlGaInP-based SDLs may be designed to emit anywhere between ~640 – 690 nm such that wavelengths between 213 nm and 230 nm may be targeted for specific applications using a similar set-up. An in-depth study of the nonlinear conversion has been carried out to understand the limitations of the set-up, namely large walk-off angles for phase-matching in the nonlinear crystals, and the potential for increasing the output power to several milli-Watts. This is, to the authors' knowledge, the first implementation of intracavity frequency tripling in a visible SDL and the shortest wavelength emitted from an SDL system

Continuous-wave semiconductor disk laser emitting at 224 nm via intracavity frequency tripling

We present frequency tripling of a tunable continuous-wave red AlGaInP semiconductor disk laser. From a fundamental beam at 674 nm, output power up to ~100 μW and laser tunability over 1.8 nm are reported

A General Optimization Technique for High Quality Community Detection in Complex Networks

Recent years have witnessed the development of a large body of algorithms for community detection in complex networks. Most of them are based upon the optimization of objective functions, among which modularity is the most common, though a number of alternatives have been suggested in the scientific literature. We present here an effective general search strategy for the optimization of various objective functions for community detection purposes. When applied to modularity, on both real-world and synthetic networks, our search strategy substantially outperforms the best existing algorithms in terms of final scores of the objective function; for description length, its performance is on par with the original Infomap algorithm. The execution time of our algorithm is on par with non-greedy alternatives present in literature, and networks of up to 10,000 nodes can be analyzed in time spans ranging from minutes to a few hours on average workstations, making our approach readily applicable to tasks which require the quality of partitioning to be as high as possible, and are not limited by strict time constraints. Finally, based on the most effective of the available optimization techniques, we compare the performance of modularity and code length as objective functions, in terms of the quality of the partitions one can achieve by optimizing them. To this end, we evaluated the ability of each objective function to reconstruct the underlying structure of a large set of synthetic and real-world networks.Comment: MAIN text: 14 pages, 4 figures, 1 table Supplementary information: 19 pages, 8 figures, 5 table

Temporal and spatial variations in freshwater 14C reservoir effects: Lake Myvatn, Northern Iceland

Lake Mývatn is an interior highland lake in northern Iceland that forms a unique ecosystem of international scientific importance and is surrounded by a landscape rich in archaeological and palaeoenvironmental sites. A significant Freshwater 14C Reservoir Effect (FRE) has been identified in carbon from the lake at some Norse (c.870-1000 AD) archaeological sites in the wider region (Mývatnssveit). Previous AMS measurements indicated this FRE was ~1500-1900 14C years. Here we present the results of a study using stable isotope and 14C measurements to quantify the Mývatn FRE for both the Norse and modern periods. This work has identified a temporally variable FRE that is greatly in excess of previous assessments. New, paired samples of contemporaneous bone from terrestrial herbivores and omnivores (including humans) from Norse sites demonstrate at least some omnivore diets incorporated sufficient freshwater resources to result in a herbivore-omnivore age offset of up to 400 14C yrs. Modern samples of benthic detritus, aquatic plants, zooplankton, invertebrates and freshwater fish indicate an FRE in excess of 5000 14C yrs in some species. Likely geothermal mechanisms for this large FRE are discussed, along with implications for both chronological reconstruction and integrated investigation of stable and radioactive isotop