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188 Publications visible to you, out of a total of 188
Indications for potential parent-of-origin effects within the FTO gene
Genetical Statistics and Systems Biology

Abstract (Expand)

Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information … on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P\leq0.05) depending on parental origin-among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P\leq0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings.   Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P\leq0.05) depending on parental origin–among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P\leq0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings. //  Genome-Wide Association Studies (GWAS) were successfully applied to discover associations with obesity. However, the GWAS design is usually based on unrelated individuals and inheritance information on the parental origin of the alleles is missing. Taking into account parent-of-origin may provide further insights into the genetic mechanisms contributing to obesity. We hypothesized that there may be variants within the robustly replicated fat mass and obesity associated (FTO) gene that may confer different risk for obesity depending on transmission from mother or father. Genome-wide genotypes and pedigree information from the Sorbs population were used. Phased genotypes among 525 individuals were generated by AlphaImpute. Subsequently, 22 SNPs within FTO introns 1 to 3 were selected and parent-of-origin specific association analyses were performed using PLINK. Interestingly, we identified several SNPs conferring different genetic effects (P\leq0.05) depending on parental origin–among them, rs1861868, rs1121980 and rs9939973 (all in intron 1). To confirm our findings, we investigated the selected variants in 705 German trios comprising an (extremely) obese child or adolescent and both parents. Again, we observed evidence for POE effects in intron 2 and 3 (P\leq0.05) as indicated by the parental asymmetry test. Our results suggest that the obesity risk transmitted by several FTO variants may depend on the parental origin of the allele. Larger family-based studies are warranted to replicate our findings.

Authors: Xuanshi Liu, Anke Hinney, Markus Scholz, André Scherag, Anke Tönjes, Michael Stumvoll, Peter F. Stadler, Johannes Hebebrand, Yvonne Böttcher

Date Published: 20th Mar 2015

Publication Type: Journal article

Monitoring Disease Progression and Therapeutic Response in a Disseminated Tumor Model for Non-Hodgkin Lymphoma by Bioluminescence Imaging
Genetical Statistics and Systems Biology

Abstract (Expand)

Xenograft tumor models are widely studied in cancer research. Our aim was to establish and apply a model for aggressive CD20-positive B-cell non-Hodgkin lymphomas, enabling us to monitor tumor growth … and shrinkage in a noninvasive manner. By stably transfecting a luciferase expression vector, we created two bioluminescent human non-Hodgkin lymphoma cell lines, Jeko1(luci) and OCI-Ly3(luci), that are CD20 positive, a prerequisite to studying rituximab, a chimeric anti-CD20 antibody. To investigate the therapy response in vivo, we established a disseminated xenograft tumor model injecting these cell lines in NOD/SCID mice. We observed a close correlation of bioluminescence intensity and tumor burden, allowing us to monitor therapy response in the living animal. Cyclophosphamide reduced tumor burden in mice injected with either cell line in a dose-dependent manner. Rituximab alone was effective in OCI-Ly3(luci)-injected mice and acted additively in combination with cyclophosphamide. In contrast, it improved the therapeutic outcome of Jeko1(luci)-injected mice only in combination with cyclophosphamide. We conclude that well-established bioluminescence imaging is a valuable tool in disseminated xenograft tumor models. Our model can be translated to other cell lines and used to examine new therapeutic agents and schedules.

Authors: Margarethe Köberle, Kristin Müller, Manja Kamprad, Friedemann Horn, Markus Scholz

Date Published: 2015

Publication Type: Journal article

Modelling chemotherapy effects on granulopoiesis.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many … parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and -dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far. RESULTS: Model assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters. CONCLUSION: We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment.

Authors: S. Schirm, C. Engel, M. Loeffler, M. Scholz

Date Published: 24th Dec 2014

Publication Type: Not specified

Human Diseases: leukopenia

Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin
Genetical Statistics and Systems Biology

Abstract (Expand)

Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis … of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p\textless5.0\times10-8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8\times10-14, beta = -0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p\textless0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.

Authors: Anke Tönjes, Markus Scholz, Jana Breitfeld, Carola Marzi, Harald Grallert, Arnd Gross, Claes Ladenvall, Dorit Schleinitz, Kerstin Krause, Holger Kirsten, Esa Laurila, Jennifer Kriebel, Barbara Thorand, Wolfgang Rathmann, Leif Groop, Inga Prokopenko, Bo Isomaa, Frank Beutner, Jürgen Kratzsch, Joachim Thiery, Mathias Fasshauer, Nora Klöting, Christian Gieger, Matthias Blüher, Michael Stumvoll, Peter Kovacs

Date Published: 18th Dec 2014

Publication Type: Journal article

Ycasd - a tool for capturing and scaling data from graphical representations
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnMathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that … clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures.\backslashr\backslashnRESULTS\backslashr\backslashnAfter describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnWe conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses. BACKGROUND Mathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures. RESULTS After describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling. CONCLUSIONS We conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses. BACKGROUND Mathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures. RESULTS After describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling. CONCLUSIONS We conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses. BACKGROUND Mathematical modelling of biological processes often requires a large variety of different data sets for parameter estimation and validation. It is common practice that clinical data are not available in raw formats but are provided as graphical representations. Hence, in order to include these data into environments used for model simulations and statistical analyses, it is necessary to extract them from their presentations in the literature. For this purpose, we developed the freely available open source tool ycasd. After establishing a coordinate system by simple axes definitions, it supports convenient retrieval of data points from arbitrary figures. RESULTS After describing the general functionality and providing an overview of the programme interface, we demonstrate on an example how to use ycasd. A major advantage of ycasd is that it does not require a certain input file format to open and process figures. All options of ycasd are accessible through a single window which eases handling and speeds up data extraction. For subsequent processing of extracted data points, results can be formatted as a Matlab or an R matrix. We extensively compare the functionality and other features of ycasd with other publically available tools. Finally, we provide a short summary of our experiences with ycasd in the context of modelling. CONCLUSIONS We conclude that our tool is suitable for convenient and accurate data retrievals from graphical representations such as papers. Comparison of tools reveals that ycasd is a good compromise between easy and quick capturing of scientific data from publications and complexity. Our tool is routinely applied in the context of biological modelling, where numerous time series data are required to develop models. The software can also be useful for other kinds of analyses for which published data are required but are not available in raw formats such as systematic reviews and meta-analyses.

Authors: Arnd Gross, Sibylle Schirm, Markus Scholz

Date Published: 1st Dec 2014

Publication Type: Journal article

Impact of pre-imputation SNP-filtering on genotype imputation results
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Imputation of partially missing or unobserved genotypes is an indispensable tool for SNP data analyses. However, research and understanding of the impact of initial SNP-data quality control …l on imputation results is still limited. In this paper, we aim to evaluate the effect of different strategies of pre-imputation quality filtering on the performance of the widely used imputation algorithms MaCH and IMPUTE. RESULTS We considered three scenarios: imputation of partially missing genotypes with usage of an external reference panel, without usage of an external reference panel, as well as imputation of completely un-typed SNPs using an external reference panel. We first created various datasets applying different SNP quality filters and masking certain percentages of randomly selected high-quality SNPs. We imputed these SNPs and compared the results between the different filtering scenarios by using established and newly proposed measures of imputation quality. While the established measures assess certainty of imputation results, our newly proposed measures focus on the agreement with true genotypes. These measures showed that pre-imputation SNP-filtering might be detrimental regarding imputation quality. Moreover, the strongest drivers of imputation quality were in general the burden of missingness and the number of SNPs used for imputation. We also found that using a reference panel always improves imputation quality of partially missing genotypes. MaCH performed slightly better than IMPUTE2 in most of our scenarios. Again, these results were more pronounced when using our newly defined measures of imputation quality. CONCLUSION Even a moderate filtering has a detrimental effect on the imputation quality. Therefore little or no SNP filtering prior to imputation appears to be the best strategy for imputing small to moderately sized datasets. Our results also showed that for these datasets, MaCH performs slightly better than IMPUTE2 in most scenarios at the cost of increased computing time.

Authors: Nab Raj Roshyara, Holger Kirsten, Katrin Horn, Peter Ahnert, Markus Scholz

Date Published: 1st Dec 2014

Publication Type: Journal article

Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression // Cellular adhesion gene SELP is associated with rheumatoid arthritis and displays differential allelic expression
Genetical Statistics and Systems Biology

Abstract (Expand)

In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single … nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p\textless10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA. In rheumatoid arthritis (RA), a key event is infiltration of inflammatory immune cells into the synovial lining, possibly aggravated by dysregulation of cellular adhesion molecules. Therefore, single nucleotide polymorphisms of 14 genes involved in cellular adhesion processes (CAST, ITGA4, ITGB1, ITGB2, PECAM1, PTEN, PTPN11, PTPRC, PXN, SELE, SELP, SRC, TYK2, and VCAM1) were analyzed for association with RA. Association analysis was performed consecutively in three European RA family sample groups (Nfamilies = 407). Additionally, we investigated differential allelic expression, a possible functional consequence of genetic variants. SELP (selectin P, CD62P) SNP-allele rs6136-T was associated with risk for RA in two RA family sample groups as well as in global analysis of all three groups (ptotal = 0.003). This allele was also expressed preferentially (p\textless10-6) with a two- fold average increase in regulated samples. Differential expression is supported by data from Genevar MuTHER (p1 = 0.004; p2 = 0.0177). Evidence for influence of rs6136 on transcription factor binding was also found in silico and in public datasets reporting in vitro data. In summary, we found SELP rs6136-T to be associated with RA and with increased expression of SELP mRNA. SELP is located on the surface of endothelial cells and crucial for recruitment, adhesion, and migration of inflammatory cells into the joint. Genetically determined increased SELP expression levels might thus be a novel additional risk factor for RA.

Authors: Jana Burkhardt, Mechthild Blume, Elisabeth Petit-Teixeira, Vitor Hugo Teixeira, Anke Steiner, Elfi Quente, Grit Wolfram, Markus Scholz, Céline Pierlot, Paola Migliorini, Stefano Bombardieri, Alejandro Balsa, René Westhovens, Pilar Barrera, Timothy R D J Radstake, Helena Alves, Thomas Bardin, Bernard Prum, Frank Emmrich, François Cornelis, Peter Ahnert, Holger Kirsten

Date Published: 22nd Aug 2014

Publication Type: Journal article

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