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227 Publications visible to you, out of a total of 227
Complexin2 modulates working memory-related neural activity in patients with schizophrenia
Genetical Statistics and Systems Biology

Abstract (Expand)

The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight … into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults.   The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults.   The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults. //  The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in Cplx2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as ’neural inefficiency,’ these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults.

Authors: Johanna Hass, Esther Walton, Holger Kirsten, Jessica Turner, Rick Wolthusen, Veit Roessner, Scott R. Sponheim, Daphne Holt, Randy Gollub, Vince D. Calhoun, Stefan Ehrlich

Date Published: 1st 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

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

Three gangliogliomas: results of GTG-banding, SKY, genome-wide high resolution SNP-array, gene expression and review of the literature.
Genetical Statistics and Systems Biology

Abstract (Expand)

According to the World Health Organization gangliogliomas are classified as well-differentiated and slowly growing neuroepithelial tumors, composed of neoplastic mature ganglion and glial cells. It is … the most frequent tumor entity observed in patients with long-term epilepsy. Comprehensive cytogenetic and molecular cytogenetic data including high-resolution genomic profiling (single nucleotide polymorphism (SNP)-array) of gangliogliomas are scarce but necessary for a better oncological understanding of this tumor entity. For a detailed characterization at the single cell and cell population levels, we analyzed genomic alterations of three gangliogliomas using trypsin-Giemsa banding (GTG-banding) and by spectral karyotyping (SKY) in combination with SNP-array and gene expression array experiments. By GTG and SKY, we could confirm frequently detected chromosomal aberrations (losses within chromosomes 10, 13 and 22; gains within chromosomes 5, 7, 8 and 12), and identify so far unknown genetic aberrations like the unbalanced non-reciprocal translocation t(1;18)(q21;q21). Interestingly, we report on the second so far detected ganglioglioma with ring chromosome 1. Analyses of SNP-array data from two of the tumors and respective germline DNA (peripheral blood) identified few small gains and losses and a number of copy-neutral regions with loss of heterozygosity (LOH) in germline and in tumor tissue. In comparison to germline DNA, tumor tissues did not show substantial regions with significant loss or gain or with newly developed LOH. Gene expression analyses of tumor-specific genes revealed similarities in the profile of the analyzed samples regarding different relevant pathways. Taken together, we describe overlapping but also distinct and novel genetic aberrations of three gangliogliomas.

Authors: L. X. Xu, H. Holland, H. Kirsten, P. Ahnert, W. Krupp, M. Bauer, R. Schober, W. Mueller, D. Fritzsch, J. Meixensberger, R. Koschny

Date Published: 8th Nov 2014

Publication Type: Journal article

Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study.
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE: Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with … variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort. DESIGN: We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype-phenotype relationships. RESULTS: Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51). CONCLUSIONS: The single-nucleotide polymorphisms rs10273639 at the PRSS1-PRSS2 locus and rs7057398 and rs12688220 at the CLDN2-MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients.

Authors: M. H. Derikx, P. Kovacs, M. Scholz, E. Masson, J. M. Chen, C. Ruffert, P. Lichtner, R. H. Te Morsche, G. M. Cavestro, C. Ferec, J. P. Drenth, H. Witt, J. Rosendahl

Date Published: 26th Sep 2014

Publication Type: Journal article

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