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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.
The origin of Galactic cosmic rays is a century-long puzzle. Indirect evidence points to their acceleration by supernova shockwaves, but we know little of their escape from the shock and their evolution through the turbulent medium surrounding massive stars. Gamma rays can probe their spreading through the ambient gas and radiation fields. The Fermi Large Area Telescope (LAT) has observed the star-forming region of Cygnus X. The 1- to 100-gigaelectronvolt images reveal a 50-parsec-wide cocoon of freshly accelerated cosmic rays that flood the cavities carved by the stellar winds and ionization fronts from young stellar clusters. It provides an example to study the youth of cosmic rays in a superbubble environment before they merge into the older Galactic population.
A novel common variant in DCST2 is associated with length in early life and height in adulthood
(2015)
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
A search for enhanced very high energy GAMMA-RAY emission from the 2013 march crab nebula flare
(2014)
In 2013 March, a flaring episode from the Crab Nebula lasting similar to 2 weeks was detected by Fermi-LAT (Large Area Telescope on board the Fermi Gamma-ray Space Telescope). The Very Energetic Radiation Imaging Telescope Array System (VERITAS) provides simultaneous observations throughout this period. During the flare, Fermi-LAT detected a 20 fold increase in flux above the average synchrotron flux >100 MeV seen from the Crab Nebula. Simultaneous measurements with VERITAS are consistent with the non-variable long-term average Crab Nebula flux at TeV energies. Assuming a linear correlation between the very high energy flux change >1 TeV and the flux change seen in the Fermi-LAT band >100 MeV during the period of simultaneous observations, the linear correlation factor can be constrained to be at most 8.6 x 10(-3) with 95% confidence.
We present the results of 71.6 hr of observations of the Geminga pulsar (PSR J0633+1746) with the VERITAS very-high-energy gamma-ray telescope array. Data taken with VERITAS between 2007 November and 2013 February were phase-folded using a Geminga pulsar timing solution derived from data recorded by the XMM-Newton and Fermi-LAT space telescopes. No significant pulsed emission above 100 GeV is observed, and we report upper limits at the 95% confidence level on the integral flux above 135 GeV (spectral analysis threshold) of 4.0x10(-13) s(-1) cm(-2) and 1.7 x 10(-13) s(-1) cm(-2) for the two principal peaks in the emission profile. These upper limits, placed in context with phase-resolved spectral energy distributions determined from 5 yr of data from the Fermi-Large Area Telescope (LAT), constrain possible hardening of the Geminga pulsar emission spectra above similar to 50 GeV.
A SEARCH FOR VERY HIGH ENERGY GAMMA RAYS FROM THE MISSING LINK BINARY PULSAR J1023+0038 WITH VERITAS
(2016)
The binary millisecond radio pulsar PSR J1023+0038 exhibits many characteristics similar to the gamma-ray binary system PSR B1259-63/LS 2883, making it an ideal candidate for the study of high-energy nonthermal emission. It has been the subject of multiwavelength campaigns following the disappearance of the pulsed radio emission in 2013 June, which revealed the appearance of an accretion disk around the neutron star. We present the results of very high energy (VHE) gamma-ray observations carried out by the Very Energetic Radiation Imaging Telescope Array System before and after this change of state. Searches for steady and pulsed emission of both data sets yield no significant gamma-ray signal above 100 GeV, and upper limits are given for both a steady and pulsed gamma-ray flux. These upper limits are used to constrain the magnetic field strength in the shock region of the PSR J1023+0038 system. Assuming that VHE gamma rays are produced via an inverse Compton mechanism in the shock region, we constrain the shock magnetic field to be greater than similar to 2 G before the disappearance of the radio pulsar and greater than similar to 10 G afterward.
The Great Nebula in Carina provides an exceptional view into the violent massive star formation and feedback that typifies giant H II regions and starburst galaxies. We have mapped the Carina star-forming complex in X-rays, using archival Chandra data and a mosaic of 20 new 60 ks pointings using the Chandra X-ray Observatory's Advanced CCD Imaging Spectrometer, as a testbed for understanding recent and ongoing star formation and to probe Carina's regions of bright diffuse X-ray emission. This study has yielded a catalog of properties of > 14,000 X-ray point sources;> 9800 of them have multiwavelength counterparts. Using Chandra's unsurpassed X-ray spatial resolution, we have separated these point sources from the extensive, spatially-complex diffuse emission that pervades the region; X-ray properties of this diffuse emission suggest that it traces feedback from Carina's massive stars. In this introductory paper, we motivate the survey design, describe the Chandra observations, and present some simple results, providing a foundation for the 15 papers that follow in this special issue and that present detailed catalogs, methods, and science results.
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.
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.