| 1. |
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- 2019
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Journal article (peer-reviewed)
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| 2. |
- Aliu, E., et al.
(author)
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Long-term TeV and X-ray Observations of the Gamma-ray Binary HESS J0632+057
- 2014
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 780:2
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Journal article (peer-reviewed)abstract
- HESS J0632+057 is the only gamma-ray binary known so far whose position in the sky allows observations with ground-based observatories in both thenorthern and southern hemispheres. Here we report on long-term observations of HESS J0632+057 conducted with the Very Energetic Radiation Imaging Telescope Array System and High Energy Stereoscopic System Cherenkov telescopes and the X-ray satellite Swift, spanning a time range from 2004 to 2012 and covering most of the system's orbit. The very-high-energy (VHE) emission is found to be variable and is correlated with that at X-ray energies. An orbital period of 315(-4)(+6) days is derived from the X-ray data set, which is compatible with previous results, P = (321 +/- 5) days. The VHE light curve shows a distinct maximum at orbital phases close to 0.3, or about 100 days after periastron passage, which coincides with the periodic enhancement of the X-rayemission. Furthermore, the analysis of the TeV data shows for the first time a statistically significant (> 6.5 sigma) detection at orbital phases 0.6-0.9. Theobtained gamma-ray and X-ray light curves and the correlation of the source emission at these two energy bands are discussed in the context of the recent ephemeris obtained for the system. Our results are compared to those reported for other gamma-ray binaries.
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| 3. |
- Collaboration, H. E. S. S., et al.
(author)
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HESS observations of the Crab during its March 2013 GeV gamma-ray flare
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 562, s. Article ID: UNSP L4-
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Journal article (peer-reviewed)abstract
- Context. On March 4, 2013 the Fermi-EAT and AGILE reported a flare from the direction of the Crab nebula in which the high-energy (HE; E > 100 MeV) flux was six times above its quiescent level. Simultaneous observations in other energy bands give us hints about the emission processes during the flare episode and the physics of pulsar wind nebulae in general. Aims. We search for variability in the emission of the Crab nebula at very-high energies (VHF,; E > 100 GeV), using contemporaneous data taken with the H.E.S.S. array of Cherenkov telescopes. Methods. Observational data taken with the H.E.S.S. instrument on five consecutive days during the flare were analysed for the flux and spectral shape of the emission from the Crab nebula. Night-wise light curves are presented with energy thresholds of 1 TeV and 5 TeV. Results. The observations conducted with H.E.S.S. on March 6 to March 10, 2013 show no significant changes in the flux. They limit the variation in the integral flux above 1 TeV to less than 63% and the integral flux above 5 TeV to less than 78% at a 95% confidence level.
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| 4. |
- Abramowski, A., et al.
(author)
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Flux upper limits for 47 AGN observed with HESS in 2004-2011
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 564, s. A9-
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Journal article (peer-reviewed)abstract
- Context. About 40% of the observation time of the High Energy Stereoscopic System (H.E.S.S.) is dedicated to studying active galactic nuclei (AGN), with the aim of increasing the sample of known extragalactic very-high-energy (VHE, E > 100 GeV) sources and constraining the physical processes at play in potential emitters. Aims. H.E.S.S. observations of AGN, spanning a period from April 2004 to December 2011, are investigated to constrain their gamma-ray fluxes. Only the 47 sources without significant excess detected at the position of the targets are presented. Methods. Upper limits on VHE fluxes of the targets were computed and a search for variability was performed on the nightly time scale. Results. For 41 objects, the flux upper limits we derived are the most constraining reported to date. These constraints at VHE are compared with the flux level expected from extrapolations of Fermi-LAT measurements in the two-year catalog of AGN. The H.E.S.S. upper limits are at least a factor of two lower than the extrapolated Fermi-LAT fluxes for 11 objects Taking into account the attenuation by the extragalactic background light reduces the tension for all but two of them, suggesting intrinsic curvature in the high-energy spectra of these two AGN. Conclusions. Compilation efforts led by current VHE instruments are of critical importance for target-selection strategies before the advent of the Cherenkov Telescope Array (CTA).
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| 5. |
- Abramowski, A., et al.
(author)
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HESS J1640-465-an exceptionally luminous TeV gamma-ray supernova remnant
- 2014
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 439:3, s. 2828-2836
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Journal article (peer-reviewed)abstract
- The results of follow-up observations of the TeV gamma-ray source HESS J1640-465 from 2004 to 2011 with the High Energy Stereoscopic System (HESS) are reported in this work. The spectrum is well described by an exponential cut-off power law with photon index Gamma = 2.11 +/- 0.09(stat) +/- 0.10(sys), and a cut-off energy of E-2 = 6.0(-1.2)(+2.0) TeV. The TeV emission is significantly extended and overlaps with the northwestern part of the shell of the SNR G338.3-0.0. The new HESS results, a re-analysis of archival XMM-Newton data and multiwavelength observations suggest that a significant part of the gamma-ray emission from HESS J1640-465 originates in the supernova remnant shell. In a hadronic scenario, as suggested by the smooth connection of the GeV and TeV spectra, the product of total proton energy and mean target density could be as high as W(p)n(H) similar to 4 x 10(52)(d/10kpc)(2) erg cm(-3).
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| 6. |
- Abramowski, A., et al.
(author)
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HESS J1818-154, a new composite supernova remnant discovered in TeV gamma rays and X-rays
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 562, s. 562-
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Journal article (peer-reviewed)abstract
- Composite supernova remnants (SNRs) constitute a small subclass of the remnants of massive stellar explosions where non-thermal radiation is observed from both the expanding shell-like shock front and from a pulsar wind nebula (PWN) located inside of the SNR. These systems represent a unique evolutionary phase of SNRs where observations in the radio, X-ray, and gamma-ray regimes allow the study of the co-evolution of both these energetic phenomena. In this article, we report results from observations of the shell-type SNR G15.4+0.1 performed with the High Energy Stereoscopic System (H. E. S. S.) and XMM-Newton. A compact TeV gamma-ray source, HESS J1818-154, located in the center and contained within the shell of G15.4+0.1 is detected by H. E. S. S. and featurs a spectrum best represented by a power-law model with a spectral index of -2.3 +/- 0.3(stat) +/- 0.2(sys) and an integral flux of F(>0.42 TeV) = (0.9 +/- 0.3(stat) +/- 0.2(sys)) x 10(-12) cm(-2) s(-1). Furthermore, a recent observation with XMM-Newton reveals extended X-ray emission strongly peaked in the center of G15.4+0.1. The X-ray source shows indications of an energy-dependent morphology featuring a compact core at energies above 4 keV and more extended emission that fills the entire region within the SNR at lower energies. Together, the X-ray and VHE gamma-ray emission provide strong evidence of a PWN located inside the shell of G15.4+0.1 and this SNR can therefore be classified as a composite based on these observations. The radio, X-ray, and gamma-ray emission from the PWN is compatible with a one-zone leptonic model that requires a low average magnetic field inside the emission region. An unambiguous counterpart to the putative pulsar, which is thought to power the PWN, has been detected neither in radio nor in X-ray observations of G15.4+0.1.
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| 7. |
- Abramowski, A., et al.
(author)
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Probing the gamma-ray emission from HESS J1834-087 using HESS and Fermi LAT observations
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 574
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Journal article (peer-reviewed)abstract
- Aims. Previous observations with the High Energy Stereoscopic System (H.E.S.S.) have revealed an extended very-high-energy (VHE; E > 100 GeV) gamma-ray source, HESS J1834-087, coincident with the supernova remnant (SNR) W41. The origin of the gamma-ray emission was investigated in more detail with the H.E.S.S. array and the Large Area Telescope (LAT) onboard the Fermi Gamma-ray Space Telescope. Methods. The gamma-ray data provided by 61 h of observations with H.E.S.S., and four years with the Fermi LAT were analyzed, covering over five decades in energy from 1.8 GeV up to 30 TeV. The morphology and spectrum of the TeV and GeV sources were studied and multiwavelength data were used to investigate the origin of the gamma-ray emission toward W41. Results. The TeV source can be modeled with a sum of two components: one point-like and one significantly extended (sigma(TeV) = 0.17 degrees +/- 0.01 degrees), both centered on SNR W41 and exhibiting spectra described by a power law with index Gamma(TeV) similar or equal to 2.6. The GeV source detected with Fermi LAT is extended (sigma(GeV) = 0.15 degrees +/- 0.03 degrees) and morphologically matches the VHE emission. Its spectrum can be described by a power-law model with an index Gamma(GeV) = 2.15 +/- 0.12 and smoothly joins the spectrum of the whole TeV source. A break appears in the gamma-ray spectra around 100 GeV. No pulsations were found in the GeV range. Conclusions. Two main scenarios are proposed to explain the observed emission: a pulsar wind nebula (PWN) or the interaction of SNR W41 with an associated molecular cloud. X-ray observations suggest the presence of a point-like source (a pulsar candidate) near the center of the remnant and nonthermal X-ray diffuse emission that could arise from the possibly associated PWN. The PWN scenario is supported by the compatible positions of the TeV and GeV sources with the putative pulsar. However, the spectral energy distribution from radio to gamma-rays is reproduced by a one-zone leptonic model only if an excess of low-energy electrons is injected following a Maxwellian distribution by a pulsar with a high spin-down power (> 10(37) erg s(-1)). This additional low-energy component is not needed if we consider that the point-like TeV source is unrelated to the extended GeV and TeV sources. The interacting SNR scenario is supported by the spatial coincidence between the gamma-ray sources, the detection of OH (1720 MHz) maser lines, and the hadronic modeling.
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| 8. |
- Abramowski, A., et al.
(author)
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Search for TeV Gamma-ray Emission from GRB 100621A, an extremely bright GRB in X-rays, with HESS
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 565, s. 1-6
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Journal article (peer-reviewed)abstract
- The long gamma-ray burst (GRB) 100621A, at the time the brightest X-ray transient ever detected by Swift-XRT in the 0.3-10 keV range, has been observed with the H.E.S.S. imaging air Cherenkov telescope array, sensitive to gamma radiation in the very-high-energy (VHE, >100 GeV) regime. Due to its relatively small redshift of z similar to 0.5, the favourable position in the southern sky and the relatively short follow-up time (<700 s after the satellite trigger) of the H.E.S.S. observations, this GRB could be within the sensitivity reach of the HESS. instrument. The analysis of the HESS. data shows no indication of emission and yields an integral flux upper limit above similar to 380 GeV of 4.2 x 10(-12) cm(-2) s(-1) s (95% confidence level), assuming a simple Band function extension model. A comparison to a spectral-temporal model, normalised to the prompt flux at sub-MeV energies, constraints the existence of a temporally extended and strong additional hard power law, as has been observed in the other bright X-ray GRB 130427A. A comparison between the HESS. upper limit and the contemporaneous energy output in X-rays constrains the ratio between the X-ray and VHE gamma-ray fluxes to be greater than 0.4. This value is an important quantity for modelling the afterglow and can constrain leptonic emission scenarios, where leptons are responsible for the X-ray emission and might produce VHE gamma rays.
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| 9. |
- Abramowski, A., et al.
(author)
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TeV gamma-ray observations of the young synchrotron-dominated SNRs G1.9+0.3 and G330.2+1.0 with HESS
- 2014
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 441:1, s. 790-799
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Journal article (peer-reviewed)abstract
- The non-thermal nature of the X-ray emission from the shell-type supernova remnants (SNRs) G1.9+0.3 and G330.2+1.0 is an indication of intense particle acceleration in the shock fronts of both objects. This suggests that the SNRs are prime candidates for very-high-energy (VHE; E > 0.1 TeV) gamma-ray observations. G1.9+0.3, recently established as the youngest known SNR in the Galaxy, also offers a unique opportunity to study the earliest stages of SNR evolution in the VHE domain. The purpose of this work is to probe the level of VHE gamma-ray emission from both SNRs and use this to constrain their physical properties. Observations were conducted with the H. E. S. S. (High Energy Stereoscopic System) Cherenkov Telescope Array over a more than six-year period spanning 2004-2010. The obtained data have effective livetimes of 67 h for G1.9+0.3 and 16 h for G330.2+1.0. The data are analysed in the context of the multiwavelength observations currently available and in the framework of both leptonic and hadronic particle acceleration scenarios. No significant gamma-ray signal from G1.9+0.3 or G330.2+1.0 was detected. Upper limits (99 per cent confidence level) to the TeV flux from G1.9+0.3 and G330.2+1.0 for the assumed spectral index Gamma = 2.5 were set at 5.6 x 10(-1)3 cm(-2) s(-1) above 0.26 TeV and 3.2 x 10(-12) cm(-2) s(-1) above 0.38 TeV, respectively. In a one-zone leptonic scenario, these upper limits imply lower limits on the interior magnetic field to B-G1.9 greater than or similar to 12 mu G for G1.9+0.3 and to B-G330 greater than or similar to 8 mu G for G330.2+1.0. In a hadronic scenario, the low ambient densities and the large distances to the SNRs result in very low predicted fluxes, for which the H.E.S.S. upper limits are not constraining.
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| 10. |
- Abramowski, A., et al.
(author)
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The high-energy gamma-ray emission of AP Librae
- 2015
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 573
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Journal article (peer-reviewed)abstract
- The gamma-ray spectrum of the low-frequency-peaked BL Lac (LBL) object AP Librae is studied, following the discovery of very-high-energy (VHE; E > 100 GeV) gamma-ray emission up to the TeV range by the H.E.S.S. experiment. Thismakes AP Librae one of the few VHE emitters of the LBL type. The measured spectrum yields a flux of (8.8 +/- 1.5(stat) +/- 1.8(sys)) x 10(-12) cm(-2) s(-1) above 130 GeV and a spectral index of Gamma = 2.65 +/- 0.19(stat) +/- 0.20(sys). This study also makes use of Fermi-LAT observations in the high energy (HE, E > 100 MeV) range, providing the longest continuous light curve (5 years) ever published on this source. The source underwent a flaring event between MJD 56 306-56 376 in the HE range, with a flux increase of a factor of 3.5 in the 14 day bin light curve and no significant variation in spectral shape with respect to the low-flux state. While the H.E.S.S. and (low state) Fermi-LAT fluxes are in good agreement where they overlap, a spectral curvature between the steep VHE spectrum and the Fermi-LAT spectrum is observed. The maximum of the gamma-ray emission in the spectral energy distribution is located below the GeV energy range.
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| 11. |
- Vos, Theo, et al.
(author)
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Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013
- 2015
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In: The Lancet. - 1474-547X .- 0140-6736. ; 386:9995, s. 743-800
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Journal article (peer-reviewed)abstract
- Background Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013. Methods Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries. Findings Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2.4 billion and 1.6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537.6 million in 1990 to 764.8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114.87 per 1000 people to 110.31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21.1% in 1990 to 31.2% in 2013. Interpretation Ageing of the world's population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.
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| 12. |
- Wang, Haidong, et al.
(author)
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Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
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Journal article (peer-reviewed)abstract
- BACKGROUND: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.METHODS: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).FINDINGS: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.INTERPRETATION: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.
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| 13. |
- Asselbergs, Folkert W., et al.
(author)
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Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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| 14. |
- Kassebaum, Nicholas J., et al.
(author)
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Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1603-1658
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Journal article (peer-reviewed)abstract
- Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs off set by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2.9 years (95% uncertainty interval 2.9-3.0) for men and 3.5 years (3.4-3.7) for women, while HALE at age 65 years improved by 0.85 years (0.78-0.92) and 1.2 years (1.1-1.3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum.
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| 15. |
- Sumaila, U. Rashid, et al.
(author)
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WTO must ban harmful fisheries subsidies
- 2021
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Journal article (other academic/artistic)
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| 16. |
- Evangelou, Evangelos, et al.
(author)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
-
Journal article (peer-reviewed)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 17. |
- Wheeler, Eleanor, et al.
(author)
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Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis
- 2017
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In: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9
-
Journal article (peer-reviewed)abstract
- Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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| 18. |
- Wormser, David, et al.
(author)
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Adult height and the risk of cause-specific death and vascular morbidity in 1 million people : individual participant meta-analysis
- 2012
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 41:5, s. 1419-1433
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Journal article (peer-reviewed)abstract
- BackgroundThe extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.MethodsWe calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.ResultsFor people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.ConclusionAdult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
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| 19. |
- Sung, Yun Ju, et al.
(author)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Journal article (peer-reviewed)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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| 20. |
- Wain, Louise V., et al.
(author)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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In: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Journal article (peer-reviewed)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 21. |
- Peloso, Gina M, et al.
(author)
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Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 223-232
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Journal article (peer-reviewed)abstract
- Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121(∗)], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.
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| 22. |
- Tinetti, G., et al.
(author)
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A chemical survey of exoplanets with ARIEL
- 2018
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In: Experimental Astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 46:1, s. 135-209
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Journal article (peer-reviewed)abstract
- Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.
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| 23. |
- Wessel, Jennifer, et al.
(author)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Journal article (peer-reviewed)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 24. |
- de Vries, Paul S., et al.
(author)
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Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study
- 2017
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1
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Journal article (peer-reviewed)abstract
- An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10(-8) is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5x10(-8)), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
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| 25. |
- de Vries, Paul S., et al.
(author)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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In: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Journal article (peer-reviewed)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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| 26. |
- Feitosa, Mary F., et al.
(author)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
-
In: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
-
Journal article (peer-reviewed)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 27. |
- Haycock, Philip C., et al.
(author)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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In: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Journal article (peer-reviewed)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 28. |
- Roberts, Jason D., et al.
(author)
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Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
- 2019
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In: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 129:8, s. 3171-3184
-
Journal article (peer-reviewed)abstract
- Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease.
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| 29. |
- Roselli, Carolina, et al.
(author)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Journal article (peer-reviewed)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.
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| 30. |
- Sawcer, Stephen, et al.
(author)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Journal article (peer-reviewed)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 31. |
- Bauer, Ann Z., et al.
(author)
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Paracetamol use during pregnancy - a call for precautionary action
- 2021
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In: Nature Reviews Endocrinology. - : Springer Nature. - 1759-5029 .- 1759-5037. ; 17, s. 757-766
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Journal article (peer-reviewed)abstract
- Paracetamol (N-acetyl-p-aminophenol (APAP), otherwise known as acetaminophen) is the active ingredient in more than 600 medications used to relieve mild to moderate pain and reduce fever. APAP is widely used by pregnant women as governmental agencies, including the FDA and EMA, have long considered APAP appropriate for use during pregnancy when used as directed. However, increasing experimental and epidemiological research suggests that prenatal exposure to APAP might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders. Here we summarize this evidence and call for precautionary action through a focused research effort and by increasing awareness among health professionals and pregnant women. APAP is an important medication and alternatives for treatment of high fever and severe pain are limited. We recommend that pregnant women should be cautioned at the beginning of pregnancy to: forego APAP unless its use is medically indicated; consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis; and minimize exposure by using the lowest effective dose for the shortest possible time. We suggest specific actions to implement these recommendations. This Consensus Statement reflects our concerns and is currently supported by 91 scientists, clinicians and public health professionals from across the globe. A growing body of research suggests that prenatal exposure to paracetamol (APAP) might alter development and increase the risk of some reproductive, urogenital and neurodevelopmental disorders. This Consensus Statement calls for precautionary action, including a focused research effort, increasing awareness among health professionals and pregnant women and, whenever possible, minimizing use.
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| 32. |
- Bauer, Ann Z., et al.
(author)
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Paracetamol Use During Pregnancy-A Call for Precautionary Action
- 2022
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In: Obstetrical and Gynecological Survey. - : Lippincott Williams & Wilkins. - 0029-7828 .- 1533-9866. ; 77:3, s. 133-134
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Journal article (peer-reviewed)abstract
- Paracetamol, otherwise known as acetaminophen, is the active ingredient in over 600 prescription and nonprescription analgesic and antipyretic medications. Worldwide and in the United States, more than 50% and 65% of pregnant women use acetaminophen, respectively. Currently, acetaminophen is considered to be of minimal risk and appropriate for use during pregnancy by the US Food and Drug Administration and European Medicines Agency. Despite this, there exists concern that environmental exposure to pharmaceuticals including acetaminophen during fetal life may contribute to the increased rates of neurological, urogenital, and reproductive disorders.This consensus statement aimed to provide an evidence-based summary of the literature relating to neurological, urogenital, and reproductive outcomes that have been associated with maternal and perinatal use of acetaminophen. This consensus statement was created by an international multidisciplinary group consisting of experts in neurology, obstetrics/gynecologists, pediatrics, epidemiology, toxicology, endocrinology, reproductive medicine, and neurodevelopment. A literature review was conducted for studies published between 1995 and 2020, including only those with acetaminophen as an independent exposure. There is a limitation in the existing epidemiological literature addressing these questions, and future efforts are required.This consensus statement and systematic review finds evidence of significant neurodevelopmental and reproductive adverse effects of acetaminophen prenatal exposure, particularly with long-term use. It is recommended by this document that acetaminophen be used by pregnant women cautiously at the lowest effective dose for the shortest possible time and longer or higher-dose use be discussed with a health professional. It is also advised that packaging display warning labels related to the evidence discussed here.
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| 33. |
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| 34. |
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| 35. |
- Broman, Aimee Teo, et al.
(author)
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Estimating the rate of progressive visual field damage in those with open-angle glaucoma, from cross-sectional data
- 2008
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In: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 49:1, s. 66-76
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Journal article (peer-reviewed)abstract
- PURPOSE. To estimate the rate of visual field progression in open-angle glaucoma (OAG) subjects, by using data from population-based cross-sectional studies. METHODS. Subjects with OAG were identified in nine surveys of randomly sampled populations using standard criteria for glaucomatous optic neuropathy. Subjects were of European, African, Chinese, and Hispanic ethnicity. The measure of OAG damage was the mean deviation (MD) of an automated visual field test (Humphrey Field Analyzer; Carl Zeiss Meditec, Inc., Dublin, CA). The rate of progression was the mean of all subjects' damage in the worse eye divided by an average time since onset. Time since onset was estimated from age-specific prevalence rates. RESULTS. A total of 1066 subjects with OAG contributed visual field data. The mean worsening in decibels per year was: European-derived, -1.12; Hispanic, -1.26; African-derived, -1.33; and Chinese -1.56 (difference among ethnicities, P = 0.16). The mean duration of disease was lowest among Chinese persons at 10.5 years (95% CI: 8.8-12.6) and was highest in African-derived subjects at 15.4 years (95% CI: 14.6-15.9). The progression rate was not consistently related to age or gender. By combining disease duration and progression rate, the model predicted that 15% or fewer of the worse eyes would reach the end of the field damage scale in the patient's lifetime. CONCLUSIONS. The estimates of typical worsening per year in the worse eye among subjects with OAG suggested slightly more rapid progression than in some clinic-based studies. The rate did not differ significantly by ethnicity or gender, but was worse in those with known, treated OAG and in pseudophakic subjects.
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| 36. |
- Itzhaki, Ruth F., et al.
(author)
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Microbes and Alzheimer's Disease
- 2016
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 51:4, s. 979-984
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Journal article (other academic/artistic)abstract
- We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD [1–4]. Fungal infection of AD brain [5, 6] has also been described, as well as abnormal microbiota in AD patient blood [7]. The first observations of HSV1 in AD brain were reported almost three decades ago [8]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease [9, 10]. These constitute the hallmarks of AD, but whether they are causes of AD or consequences is unknown. We suggest that these are indicators of an infectious etiology. In the case of AD, it is often not realized that microbes can cause chronic as well as acute diseases; that some microbes can remain latent in the body with the potential for reactivation, the effects of which might occur years after initial infection; and that people can be infected but not necessarily affected, such that ‘controls’, even if infected, are asymptomatic
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| 37. |
- Itzhaki, Ruth F., et al.
(author)
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Microbes and Alzheimer's disease
- 2017
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In: Handbook of infection and Alzheimer's disease. - : IOS Press. - 9781614997054 - 9781614997061 ; , s. 3-8
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Book chapter (peer-reviewed)
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| 38. |
- Jallow, Muminatou, et al.
(author)
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Genome-wide and fine-resolution association analysis of malaria in West Africa.
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 657-665
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Journal article (peer-reviewed)abstract
- We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
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