| 1. |
- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 2. |
- Fuchsberger, Christian, et al.
(author)
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The genetic architecture of type 2 diabetes
- 2016
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Journal article (peer-reviewed)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 3. |
- Manning, Alisa, et al.
(author)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Journal article (peer-reviewed)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 4. |
- Reifarth, R., et al.
(author)
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Nuclear astrophysics with radioactive ions at FAIR
- 2016
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In: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 665:1
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Conference paper (peer-reviewed)abstract
- The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process beta-decay chains. These nuclei are attributed to the p and rp process. For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections. The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
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| 5. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- 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.
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| 6. |
- Clement, E., et al.
(author)
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Conceptual design of the AGATA 1 π array at GANIL
- 2017
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In: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 855, s. 1-12
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Journal article (peer-reviewed)abstract
- The Advanced GAmma Tracking Array (AGATA) has been installed at the GANIL facility, Caen-France. This setup exploits the stable and radioactive heavy-ions beams delivered by the cyclotron accelerator complex of GANIL. Additionally, it benefits from a large palette of ancillary detectors and spectrometers to address in-beam γ-ray spectroscopy of exotic nuclei. The set-up has been designed to couple AGATA with a magnetic spectrometer, charged-particle and neutron detectors, scintillators for the detection of high-energy γ rays and other devices such as a plunger to measure nuclear lifetimes. In this paper, the design and the mechanical characteristics of the set-up are described. Based on simulations, expected performances of the AGATA l π array are presented.
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| 7. |
- Heim, Wieland, et al.
(author)
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Using geolocator tracking data and ringing archives to validate citizen-science based seasonal predictions of bird distribution in a data-poor region
- 2020
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In: Global Ecology and Conservation. - : Elsevier BV. - 2351-9894. ; 24
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Journal article (peer-reviewed)abstract
- Unstructured citizen-science data are increasingly used for analysing the abundance and distribution of species. Here we test the usefulness of such data to predict the seasonal distribution of migratory songbirds, and to analyse patterns of migratory connectivity. We used bird occurrence data from eBird, one of the largest global citizen science databases, to predict the year-round distribution of eight songbird taxa (Agropsar philippensis, Calliope calliope, Cecropis daurica, Emberiza aureola, Hirundo rustica, Locustella certhiola, Oriolus chinensis, Saxicola torquatus stejnegeri) that migrate through East Asia, a region especially poor in data but globally important for the conservation of migratory land birds. Maximum entropy models were built to predict spring stopover, autumn stopover and wintering areas. Ring recovery and geolocator tracking data were then used to evaluate, how well the predicted occurrence at a given period of the annual cycle matched sites where the species were known to be present from ringing and tracking data. Predicted winter ranges were generally smaller than those on published extent-of-occurrence maps (the hitherto only available source of distribution information). There was little overlap in stopover regions. The overlap between areas predicted as suitable from the eBird data and areas that had records from geolocator tracking was high in winter, and lower for spring and autumn migration. Less than 50% of the ringing recoveries came from locations within the seasonal predicted areas, with the highest overlap in autumn. The seasonal range size of a species affected the matching of tracking/ringing data with the predictions. Strong migratory connectivity was evident in Siberian Rubythroats and Barn Swallows. We identified two migration corridors, one over the eastern mainland of China, and one along a chain of islands in the Pacific. We show that the combination of disparate data sources has great potential to gain a better understanding of the non-breeding distribution and migratory connectivity of Eastern Palearctic songbirds. Citizen-science observation data are useful even in remote areas to predict the seasonal distribution of migratory species, especially in periods when birds are sedentary and when supplemented with tracking data.
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| 8. |
- Lagou, Vasiliki, et al.
(author)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 9. |
- Moosmann, Julian, et al.
(author)
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A load frame for in situ tomography at PETRA III
- 2019
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In: Developments in X-Ray Tomography XII. - : SPIE. - 0277-786X .- 1996-756X. - 9781510629196 ; 11113
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Conference paper (other academic/artistic)abstract
- A load frame for in situ mechanical testing is developed for the microtomography end stations at the imaging beamline P05 and the high-energy material science beamline P07 of PETRA III at DESY, both operated by the Helmholtz- Zentrum Geesthacht. The load frame is fully integrated into the beamline control system and can be controlled via a feedback loop. All relevant parameters (load, displacement, temperature, etc.) are continuously logged. It can be operated in compression or tensile mode applying forces of up to 1 kN and is compatible with all contrast modalities available at IBL and HEMS i.e. conventional attenuation contrast, propagation based phase contrast and differential phase contrast using a grating interferometer. The modularity and flexibility of the load frame allows conducting a wide range of experiments. E.g. compression tests to understand the failure mechanisms in biodegradable implants in rat bone or to investigate the mechanics and kinematics of the tessellated cartilage skeleton of sharks and rays, or tensile tests to illuminate the structure-property relationship in poplar tension wood or to visualize the 3D deformation of the tendonbone insertion. We present recent results from the experiments described including machine-learning driven volume segmentation and digital volume correlation of load tomography sequences.
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| 10. |
- Moosmann, Julian, et al.
(author)
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Biodegradable magnesium-based implants in bone studied by synchrotron radiation microtomography
- 2017
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In: Developments in X-Ray Tomography XI. - : SPIE - International Society for Optical Engineering. ; 10391
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Conference paper (peer-reviewed)abstract
- Permanent implants made of titanium or its alloys are the gold standard in many orthopedic and traumatological applications due to their good biocompatibility and mechanical properties. However, a second surgical intervention is required for this kind of implants as they have to be removed in the case of children that are still growing or on patient's demand. Therefore, magnesium-based implants are considered for medical applications as they are degraded under physiological conditions. The major challenge is tailoring the degradation in a manner that is suitable for a biological environment and such that stabilization of the bone is provided for a controlled period. In order to understand failure mechanisms of magnesium-based implants in orthopedic applications and, further, to better understand the osseointegration, screw implants in bone are studied under mechanical load by means of a push-out device installed at the imaging beamline P05 of PETRA III at DESY. Conventional absorption contrast microtomography and phasecontrast techniques are applied in order to monitor the bone-to-implant interface under increasing load conditions. In this proof-of-concept study, first results from an in situ push-out experiment are presented.
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