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To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Arctic lowlands are characterized by large numbers of small waterbodies, which are known to affect surface energy budgets and the global carbon cycle. Statistical analysis of their size distributions has been hindered by the shortage of observations at sufficiently high spatial resolutions. This situation has now changed with the high-resolution (<5 m) circum-Arctic Permafrost Region Pond and Lake (PeRL) database recently becoming available. We have used this database to make the first consistent, high-resolution estimation of Arctic waterbody size distributions, with surface areas ranging from 0.0001 km(2) (100 m(2)) to 1 km(2). We found that the size distributions varied greatly across the thirty study regions investigated and that there was no single universal size distribution function (including power-law distribution functions) appropriate across all of the study regions. We did, however, find close relationships between the statistical moments (mean, variance, and skewness) of the waterbody size distributions from different study regions. Specifically, we found that the spatial variance increased linearly with mean waterbody size (R-2 = 0.97, p < 2.2e-16) and that the skewness decreased approximately hyperbolically. We have demonstrated that these relationships (1) hold across the 30 Arctic study regions covering a variety of (bio)climatic and permafrost zones, (2) hold over time in two of these study regions for which multi-decadal satellite imagery is available, and (3) can be reproduced by simulating rising water levels in a high-resolution digital elevation model. The consistent spatial and temporal relationships between the statistical moments of the waterbody size distributions underscore the dominance of topographic controls in lowland permafrost areas. These results provide motivation for further analyses of the factors involved in waterbody development and spatial distribution and for investigations into the possibility of using statistical moments to predict future hydrologic dynamics in the Arctic.
We present a new tomographic model of the mantle in the area of the 2010 M8.8 Maule earthquake and surrounding regions. Increased ray coverage provided by the aftershock data allows us to image the detailed subducting slab structure in the mantle, from the region of flat slab subduction north of the Maule rupture to the area of overlapping rupture between the 1960 M9.5 and the 2010 M8.8 events to the south. We have combined teleseismic primary and depth phase arrivals with available local arrivals to better constrain the teleseismic earthquake locations in the region, which we use to conduct nested regionalglobal tomography. The new model reveals the detailed structure of the flat slab and its transition to a more moderately dipping slab in the Maule region. South of the Maule region, a steeply dipping relic slab is imaged from similar to 200 to 1000 km depth that is distinct from the moderately dipping slab above it and from the more northerly slab at similar depths. We interpret the images as revealing both horizontal and vertical tearing of the slab at similar to 38 degrees S to explain the imaged pattern of slab anomalies in the southern portion of the model. In contrast, the transition from a horizontal to moderately subducting slab in the northern portion of the model is imaged as a continuous slab bend. We speculate that the tearing was most likely facilitated by a fracture zone in the downgoing plate or alternatively by a continental scale terrane boundary in the overriding plate.
We focus on the relation between seismic and total postseismic afterslip following the Maule M-w 8.8 earthquake on 2010 February 27 in central Chile. First, we calculate the cumulative slip released by aftershock seismicity. We do this by summing up the aftershock regions and slip estimated from scaling relations. Comparing the cumulative seismic slip with afterslip modelswe showthat seismic slip of individual aftershocks exceeds locally the inverted afterslip model from geodetic constraints. As the afterslip model implicitly contains the displacements from the aftershocks, this reflects the tendency of afterslip models to smear out the actual slip pattern. However, it also suggests that locally slip for a number of the larger aftershocks exceeds the aseismic slip in spite of the fact that the total equivalent moment of the afterslip exceeds the cumulative moment of aftershocks by a large factor. This effect, seen weakly for the Maule 2010 and also for the Tohoku 2011 earthquake, can be explained by taking into account the uncertainties of the seismicity and afterslip models. In spite of uncertainties, the hypocentral region of the Nias 2005 earthquake is suggested to release a large fraction of moment almost purely seismically. Therefore, these aftershocks are not driven solely by the afterslip but instead their slip areas have probably been stressed by interseismic loading and the mainshock rupture. In a second step, we divide the megathrust of the Maule 2010 rupture into discrete cells and count the number of aftershocks that occur within 50 km of the centre of each cell as a function of time. We then compare this number to a time-dependent afterslip model by defining the 'afterslip to aftershock ratio' (ASAR) for each cell as the slope of the best fitting line when the afterslip at time t is plotted against aftershock count. Although we find a linear relation between afterslip and aftershocks for most cells, there is significant variability in ASAR in both the downdip and along-strike directions of the megathrust. We compare the spatial distribution of ASAR with the spatial distribution of seismic coupling, coseismic slip and Bouguer gravity anomaly, and in each case we find no significant correlation.
Aims. We analyze the emission in the 0.3-30 GeV energy range of gamma-ray bursts detected with the Fermi Gamma-ray Space Telescope. We concentrate on bursts that were previously only detected with the Gamma-Ray Burst Monitor in the keV energy range. These bursts will then be compared to the bursts that were individually detected with the Large Area Telescope at higher energies.
Methods. To estimate the emission of faint GRBs we used nonstandard analysis methods and sum over many GRBs to find an average signal that is significantly above background level. We used a subsample of 99 GRBs listed in the Burst Catalog from the first two years of observation.
Results. Although most are not individually detectable, the bursts not detected by the Large Area Telescope on average emit a significant flux in the energy range from 0.3 GeV to 30 GeV, but their cumulative energy fluence is only 8% of that of all GRBs. Likewise, the GeV-to-MeV flux ratio is less and the GeV-band spectra are softer. We confirm that the GeV-band emission lasts much longer than the emission found in the keV energy range. The average allsky energy flux from GRBs in the GeV band is 6.4 x 10(-4) erg cm(-2) yr(-1) or only similar to 4% of the energy flux of cosmic rays above the ankle at 10(18.6) eV.
The Low Earth Orbit (LEO) experiment Biology and Mars Experiment (BIOMEX) is an interdisciplinary and international space research project selected by ESA. The experiment will be accommodated on the space exposure facility EXPOSE-R2 on the International Space Station (ISS) and is foreseen to be launched in 2013. The prime objective of BIOMEX is to measure to what extent biomolecules, such as pigments and cellular components, are resistant to and able to maintain their stability under space and Mars-like conditions. The results of BIOMEX will be relevant for space proven biosignature definition and for building a biosignature data base (e.g. the proposed creation of an international Raman library). The library will be highly relevant for future space missions such as the search for life on Mars. The secondary scientific objective is to analyze to what extent terrestrial extremophiles are able to survive in space and to determine which interactions between biological samples and selected minerals (including terrestrial, Moon- and Mars analogs) can be observed under space and Mars-like conditions. In this context, the Moon will be an additional platform for performing similar experiments with negligible magnetic shielding and higher solar and galactic irradiation compared to LEO. Using the Moon as an additional astrobiological exposure platform to complement ongoing astrobiological LEO investigations could thus enhance the chances of detecting organic traces of life on Mars. We present a lunar lander mission with two related objectives: a lunar lander equipped with Raman and PanCam instruments which can analyze the lunar surface and survey an astrobiological exposure platform. This dual use of testing mission technology together with geo- and astrobiological analyses will significantly increase the science return, and support the human preparation objectives. It will provide knowledge about the Moon's surface itself and, in addition, monitor the stability of life-markers, such as cells, cell components and pigments, in an extraterrestrial environment with much closer radiation properties to the surface of Mars. The combination of a Raman data base of these data together with data from LEO and space simulation experiments, will lead to further progress on the analysis and interpretation of data that we will obtain from future Moon and Mars exploration missions.