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142 Publications visible to you, out of a total of 142
Impact of genetic similarity on imputation accuracy.
LIFE - Leipzig Research Center for Civilization Diseases, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Genotype imputation is a common technique in genetic research. Genetic similarity between target population and reference dataset is crucial for high-quality results. Although several … reference panels are available, it is often not clear which is the most optimal for a particular target dataset to be imputed. Maximizing genetic similarity between study sample and intended reference panels may be the straight forward method for selecting the genetically best-matched reference. However, the impact of genetic similarity on imputation accuracy has not yet been studied in detail. RESULTS: We performed a simulation study in 20 ethnic groups obtained from POPRES. High-quality SNPs were masked and re-imputed with MaCH, MaCH-minimac and IMPUTE2 using four different HapMap reference panels (CEU, CHB-JPT, MEX and YRI). Imputation accuracy was assessed by different statistics. Genetic similarity between ethnic groups and reference populations were measured by F -statistics (F(ST)) originally proposed by Wright and G -statistics (G(ST)) introduced by Nei and others. To assess the predictive power of these measures regarding imputation accuracy, we analysed relations between them and corresponding imputation accuracy scores. We found that population genetic distances between homogeneous reference and target populations were strongly linearly correlated with resulting imputation accuracies irrespective of considered distance measure, imputation accuracy measure, missingness and imputation software used. Possible exception was African population. CONCLUSION: Usage of G(ST) or F(ST)-related measures for predicting the optimal reference panel for imputation frameworks relying on a specific reference is highly recommended. A cut-off of G(ST) < 0.01 is recommended to achieve good imputation results for high-frequency variants and small data sets. The linear relationship is less pronounced for low-frequency variants for which we also observed a dependence of imputation accuracy on the number of polymorphic sites in the reference. We also show that the software specific measures MaCH-Rsq and IMPUTE-info must be interpreted with caution if the genetic distance of target and reference population is high.

Authors: N. R. Roshyara, M. Scholz

Date Published: 22nd Jul 2015

Publication Type: Not specified

The PCBP1 gene encoding poly(rC) binding protein I is recurrently mutated in Burkitt lymphoma.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG-MYC juxtaposition. However, these translocations alone are insufficient … to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole-genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron-less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K-Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre-mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20-40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis.

Authors: R. Wagener, S. M. Aukema, M. Schlesner, A. Haake, B. Burkhardt, A. Claviez, H. G. Drexler, M. Hummel, M. Kreuz, M. Loeffler, M. Rosolowski, C. Lopez, P. Moller, J. Richter, M. Rohde, M. J. Betts, R. B. Russell, S. H. Bernhart, S. Hoffmann, P. Rosenstiel, M. Schilhabel, M. Szczepanowski, L. Trumper, W. Klapper, R. Siebert

Date Published: 16th Jul 2015

Publication Type: Not specified

Human Diseases: lymphoma

Nanoparticle uptake by macrophages in vulnerable plaques for atherosclerosis diagnosis.
LIFE Adult

Abstract (Expand)

The composition of atherosclerotic (AS) plaques is crucial concerning rupture, thrombosis and clinical events. Two plaque types are distinguished: stable and vulnerable plaques. Vulnerable plaques are … rich in inflammatory cells, mostly only M1 macrophages, and are highly susceptible to rupture. These plaques represent a high risk particularly with the standard invasive diagnosis by coronary angiography. So far there are no non-invasive low-risk clinical approaches available to detect and distinguish AS plaque types in vivo. The perspective review introduces a whole work-flow for a novel approach for non-invasive detection and classification of AS plaques using the diffusion reflection method with gold nanoparticle loaded macrophages in combination with flow and image cytometric analysis for quality assurance. Classical biophotonic methods for AS diagnosis are summarized. Phenotyping of monocytes and macrophages are discussed for specific subset labelling by nanomaterials, as well as existing studies and first experimental proofs of concept for the novel approach are shown. In vitro and in vivo detection of NP loaded macrophages (MPhi). Different ways of MPhi labelling include (1) in vitro labelling in suspension (whole blood or buffy coat) or (2) labelling of short-term MPhi cultures with re-injection of MPhi-NP into the animal to detect migration of the cells in the plaques and (3) in vivo injection of NP into the organism.

Authors: S. Melzer, R. Ankri, D. Fixler, A. Tarnok

Date Published: 26th Jun 2015

Publication Type: Not specified

Human Diseases: atherosclerosis

Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans' anomaly, in which functional … consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl(-/-) mice exhibit Jordans' anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl(-/-) mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl(-/-) mice. Mechanistically, ATGL(-/-) as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans' anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases.

Authors: S. Schlager, M. Goeritzer, K. Jandl, R. Frei, N. Vujic, D. Kolb, H. Strohmaier, J. Dorow, T. O. Eichmann, A. Rosenberger, A. Wolfler, A. Lass, E. E. Kershaw, U. Ceglarek, A. Dichlberger, A. Heinemann, D. Kratky

Date Published: 26th Jun 2015

Publication Type: Not specified

Genetic dyslexia risk variant is related to neural connectivity patterns underlying phonological awareness in children.
LIFE - Leipzig Research Center for Civilization Diseases, Genetical Statistics and Systems Biology

Abstract (Expand)

Phonological awareness is the best-validated predictor of reading and spelling skill and therefore highly relevant for developmental dyslexia. Prior imaging genetics studies link several dyslexia risk … genes to either brain-functional or brain-structural factors of phonological deficits. However, coherent evidence for genetic associations with both functional and structural neural phenotypes underlying variation in phonological awareness has not yet been provided. Here we demonstrate that rs11100040, a reported modifier of SLC2A3, is related to the functional connectivity of left fronto-temporal phonological processing areas at resting state in a sample of 9- to 12-year-old children. Furthermore, we provide evidence that rs11100040 is related to the fractional anisotropy of the arcuate fasciculus, which forms the structural connection between these areas. This structural connectivity phenotype is associated with phonological awareness, which is in turn associated with the individual retrospective risk scores in an early dyslexia screening as well as to spelling. These results suggest a link between a dyslexia risk genotype and a functional as well as a structural neural phenotype, which is associated with a phonological awareness phenotype. The present study goes beyond previous work by integrating genetic, brain-functional and brain-structural aspects of phonological awareness within a single approach. These combined findings might be another step towards a multimodal biomarker for developmental dyslexia.

Authors: M. A. Skeide, H. Kirsten, I. Kraft, G. Schaadt, B. Muller, N. Neef, J. Brauer, A. Wilcke, F. Emmrich, J. Boltze, A. D. Friederici

Date Published: 17th Jun 2015

Publication Type: Not specified

Human Diseases: dyslexia

Mortality in incident dementia - results from the German Study on Aging, Cognition, and Dementia in Primary Care Patients.
LIFE Adult

Abstract (Expand)

OBJECTIVE: Dementia is known to increase mortality, but the relative loss of life years and contributing factors are not well established. Thus, we aimed to investigate mortality in incident dementia … from disease onset. METHOD: Data were derived from the prospective longitudinal German AgeCoDe study. We used proportional hazards models to assess the impact of sociodemographic and health characteristics on mortality after dementia onset, Kaplan-Meier method for median survival times. RESULTS: Of 3214 subjects at risk, 523 (16.3%) developed incident dementia during a 9-year follow-up period. Median survival time after onset was 3.2 years (95% CI = 2.8-3.7) at a mean age of 85.0 (SD = 4.0) years (>/=2.6 life years lost compared with the general German population). Survival was shorter in older age, males other dementias than Alzheimer's, and in the absence of subjective memory complaints (SMC). CONCLUSION: Our findings emphasize that dementia substantially shortens life expectancy. Future studies should further investigate the potential impact of SMC on mortality in dementia.

Authors: S. Roehr, T. Luck, H. Bickel, C. Brettschneider, A. Ernst, A. Fuchs, K. Heser, H. H. Konig, F. Jessen, C. Lange, E. Mosch, M. Pentzek, S. Steinmann, S. Weyerer, J. Werle, B. Wiese, M. Scherer, W. Maier, S. G. Riedel-Heller

Date Published: 9th Jun 2015

Publication Type: Not specified

Human Diseases: cognitive disorder, dementia

Analysis of asthma patients for cryptococcal seroreactivity in an urban German area.
LIFE Adult

Abstract (Expand)

Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised patients but is also able to asymptomatically infect immunocompetent … individuals. C. neoformans is found ubiquitously especially in urban areas where it is spread by pigeons, and fungal exposure may predispose for asthma development already at an early age, as soon as confronted with pigeon droppings. In the study presented here, we investigated the presence of specific immunoglobulin G (IgG) against C. neoformans in sera from patients suffering from asthma in comparison to a healthy control cohort, accrued from the Leipzig Research Centre for Civilization Diseases (LIFE). For serological analysis we developed a flow cytometry (FACS) based assay specific for an acapsular strain of C. neoformans to comprehensively analyze different cryptococcal serotypes. Compared with the non-asthmatic cohort, asthmatics exhibited, as expected, an elevated level of total serum immunoglobulin E (IgE), whereas the IgG seroreactivity against C. neoformans was not significantly different among the two groups (P = .118). Nevertheless, there was a trend toward increased Cryptococcus-specific IgG antibodies in the serum of asthmatics. Additionally, in male asthmatics an increased IgG-mediated seroreactivity compared to female asthmatics was found. This points to a higher prevalence of subclinical C. neoformans infection in male asthmatics and may support the hypothesis of C. neoformans as a risk factor for the development of asthma in urban areas.

Authors: A. Grahnert, U. Muller, H. von Buttlar, R. Treudler, G. Alber

Date Published: 31st May 2015

Publication Type: Not specified

Human Diseases: asthma, allergic hypersensitivity disease

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