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1. Implementing FAIR data management within the German Network for Bioinformatics Infrastructure (de.NBI) exemplified by selected use cases

Author: Mayer, Gerhard, Müller, Wolfgang, Schork, Karin, Uszkoreit, Julian, Weidemann, Andreas, Wittig, Ulrike, Rey, Maja, Quast, Christian, Felden, Janine, Glöckner, Frank Oliver, Lange, Matthias, Arend, Daniel, Beier, Sebastian, Junker, Astrid, Scholz, Uwe, Schüler, Danuta, Kestler, Hans A, Wibberg, Daniel, Pühler, Alfred, Twardziok, Sven, Eils, Jürgen, Eils, Roland, Hoffmann, Steve, Eisenacher, Martin, Turewicz, Michael, Mayer, Gerhard, Müller, Wolfgang, Schork, Karin, Uszkoreit, Julian, Weidemann, Andreas, Wittig, Ulrike, Rey, Maja, Quast, Christian, Felden, Janine, Glöckner, Frank Oliver, Lange, Matthias, Arend, Daniel, Beier, Sebastian, Junker, Astrid, Scholz, Uwe, Schüler, Danuta, Kestler, Hans A, Wibberg, Daniel, Pühler, Alfred, Twardziok, Sven, Eils, Jürgen, Eils, Roland, Hoffmann, Steve, Eisenacher, Martin, and Turewicz, Michael
Abstract: Abstract This article describes some use case studies and self-assessments of FAIR status of de.NBI services to illustrate the challenges and requirements for the definition of the needs of adhering to the FAIR (findable, accessible, interoperable and reusable) data principles in a large distributed bioinformatics infrastructure. We address the challenge of heterogeneity of wet lab technologies, data, metadata, software, computational workflows and the levels of implementation and monitoring of FAIR principles within the different bioinformatics sub-disciplines joint in de.NBI. On the one hand, this broad service landscape and the excellent network of experts are a strong basis for the development of useful research data management plans. On the other hand, the large number of tools and techniques maintained by distributed teams renders FAIR compliance challenging.
Published: 2021

2. Reduced rate of inpatient hospital admissions in 18 german university hospitals during the COVID-19 lockdown

Author: MII-Research Group, Kapsner, Lorenz Alois, Kampf, Marvin O., Seuchter, Susanne A., Gruendner, Julian, Gulden, Christian, Mate, Sebastian, Mang, Jonathan M., Schüttler, Christina, Deppenwiese, Noemi, Krause, Linda, Zöller, Daniela, Balig, Julien, Fuchs, Timo, Fischer, Patrick, Haverkamp, Christian, Holderried, Martin, Mayer, Gerhard, Stenzhorn, Holger, Stolnicu, Ana, Storck, Michael, Storf, Holger, Zohner, Jochen, Kohlbacher, Oliver, Strzelczyk, Adam, Schüttler, Jürgen, Acker, Till, Boeker, Martin, Kaisers, Udo X., Kestler, Hans A., Prokosch, Hans-Ulrich, MII-Research Group, Kapsner, Lorenz Alois, Kampf, Marvin O., Seuchter, Susanne A., Gruendner, Julian, Gulden, Christian, Mate, Sebastian, Mang, Jonathan M., Schüttler, Christina, Deppenwiese, Noemi, Krause, Linda, Zöller, Daniela, Balig, Julien, Fuchs, Timo, Fischer, Patrick, Haverkamp, Christian, Holderried, Martin, Mayer, Gerhard, Stenzhorn, Holger, Stolnicu, Ana, Storck, Michael, Storf, Holger, Zohner, Jochen, Kohlbacher, Oliver, Strzelczyk, Adam, Schüttler, Jürgen, Acker, Till, Boeker, Martin, Kaisers, Udo X., Kestler, Hans A., and Prokosch, Hans-Ulrich
Abstract: The COVID-19 pandemic has caused strains on health systems worldwide disrupting routine hospital services for all non-COVID patients. Within this retrospective study, we analyzed inpatient hospital admissions across 18 German university hospitals during the 2020 lockdown period compared to 2018. Patients admitted to hospital between January 1 and May 31, 2020 and the corresponding periods in 2018 and 2019 were included in this study. Data derived from electronic health records were collected and analyzed using the data integration center infrastructure implemented in the university hospitals that are part of the four consortia funded by the German Medical Informatics Initiative. Admissions were grouped and counted by ICD 10 chapters and specific reasons for treatment at each site. Pooled aggregated data were centrally analyzed with descriptive statistics to compare absolute and relative differences between time periods of different years. The results illustrate how care process adoptions depended on the COVID-19 epidemiological situation and the criticality of the disease. Overall inpatient hospital admissions decreased by 35% in weeks 1 to 4 and by 30.3% in weeks 5 to 8 after the lockdown announcement compared to 2018. Even hospital admissions for critical care conditions such as malignant cancer treatments were reduced. We also noted a high reduction of emergency admissions such as myocardial infarction (38.7%), whereas the reduction in stroke admissions was smaller (19.6%). In contrast, we observed a considerable reduction in admissions for non-critical clinical situations, such as hysterectomies for benign tumors (78.8%) and hip replacements due to arthrosis (82.4%). In summary, our study shows that the university hospital admission rates in Germany were substantially reduced following the national COVID-19 lockdown. These included critical care or emergency conditions in which deferral is expected to impair clinical outcomes. Future studies are needed to deline
Published: 2021

3. Corona Health -- A Study- and Sensor-based Mobile App Platform Exploring Aspects of the COVID-19 Pandemic

Author: Beierle, Felix, Schobel, Johannes, Vogel, Carsten, Allgaier, Johannes, Mulansky, Lena, Haug, Fabian, Haug, Julian, Schlee, Winfried, Holfelder, Marc, Stach, Michael, Schickler, Marc, Baumeister, Harald, Cohrdes, Caroline, Deckert, Jürgen, Deserno, Lorenz, Edler, Johanna-Sophie, Eichner, Felizitas A., Greger, Helmut, Hein, Grit, Heuschmann, Peter, John, Dennis, Kestler, Hans A., Krefting, Dagmar, Langguth, Berthold, Meybohm, Patrick, Probst, Thomas, Reichert, Manfred, Romanos, Marcel, Störk, Stefan, Terhorst, Yannik, Weiß, Martin, Pryss, Rüdiger, Beierle, Felix, Schobel, Johannes, Vogel, Carsten, Allgaier, Johannes, Mulansky, Lena, Haug, Fabian, Haug, Julian, Schlee, Winfried, Holfelder, Marc, Stach, Michael, Schickler, Marc, Baumeister, Harald, Cohrdes, Caroline, Deckert, Jürgen, Deserno, Lorenz, Edler, Johanna-Sophie, Eichner, Felizitas A., Greger, Helmut, Hein, Grit, Heuschmann, Peter, John, Dennis, Kestler, Hans A., Krefting, Dagmar, Langguth, Berthold, Meybohm, Patrick, Probst, Thomas, Reichert, Manfred, Romanos, Marcel, Störk, Stefan, Terhorst, Yannik, Weiß, Martin, and Pryss, Rüdiger
Abstract: Physical and mental well-being during the COVID-19 pandemic is typically assessed via surveys, which might make it difficult to conduct longitudinal studies and might lead to data suffering from recall bias. Ecological momentary assessment (EMA) driven smartphone apps can help alleviate such issues, allowing for in situ recordings. Implementing such an app is not trivial, necessitates strict regulatory and legal requirements, and requires short development cycles to appropriately react to abrupt changes in the pandemic. Based on an existing app framework, we developed Corona Health, an app that serves as a platform for deploying questionnaire-based studies in combination with recordings of mobile sensors. In this paper, we present the technical details of Corona Health and provide first insights into the collected data. Through collaborative efforts from experts from public health, medicine, psychology, and computer science, we released Corona Health publicly on Google Play and the Apple App Store (in July, 2020) in 8 languages and attracted 7,290 installations so far. Currently, five studies related to physical and mental well-being are deployed and 17,241 questionnaires have been filled out. Corona Health proves to be a viable tool for conducting research related to the COVID-19 pandemic and can serve as a blueprint for future EMA-based studies. The data we collected will substantially improve our knowledge on mental and physical health states, traits and trajectories as well as its risk and protective factors over the course of the COVID-19 pandemic and its diverse prevention measures.
Published: 2021

4. Is there a role for statistics in artificial intelligence?

Author: Friedrich, Sarah, Antes, Gerd, Behr, Sigrid, Binder, Harald, Brannath, Werner, Dumpert, Florian, Ickstadt, Katja, Kestler, Hans, Lederer, Johannes, Leitgöb, Heinz, Pauly, Markus, Steland, Ansgar, Wilhelm, Adalbert, Friede, Tim, Friedrich, Sarah, Antes, Gerd, Behr, Sigrid, Binder, Harald, Brannath, Werner, Dumpert, Florian, Ickstadt, Katja, Kestler, Hans, Lederer, Johannes, Leitgöb, Heinz, Pauly, Markus, Steland, Ansgar, Wilhelm, Adalbert, and Friede, Tim
Abstract: The research on and application of artificial intelligence (AI) has triggered a comprehensive scientific, economic, social and political discussion. Here we argue that statistics, as an interdisciplinary scientific field, plays a substantial role both for the theoretical and practical understanding of AI and for its future development. Statistics might even be considered a core element of AI. With its specialist knowledge of data evaluation, starting with the precise formulation of the research question and passing through a study design stage on to analysis and interpretation of the results, statistics is a natural partner for other disciplines in teaching, research and practice. This paper aims at contributing to the current discussion by highlighting the relevance of statistical methodology in the context of AI development. In particular, we discuss contributions of statistics to the field of artificial intelligence concerning methodological development, planning and design of studies, assessment of data quality and data collection, differentiation of causality and associations and assessment of uncertainty in results. Moreover, the paper also deals with the equally necessary and meaningful extension of curricula in schools and universities.
Published: 2020

5. Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer

Author: German Cancer Aid, German Research Foundation, Ulm University, Ministry for Science and Culture of Lower Saxony, Deutsche Krebshilfe, Gout, Johann, Perkhofer, Lukas, Morawe, Mareen, Arnold, Frank, Ihle, Michaela, Biber, Stephanie, Lange, Sebastian, Roger, Elodie, Kraus, Johann M., Stifter, Katja, Hahn, Stephan A., Zamperone, Andrea, Engleitner, Thomas, Müller, Martin, Walter, Karolin, Rodriguez-Aznar, Eva, Sainz, Bruno Jr., Hermann, Patrick C., Hessmann, Elisabeth, Müller, Sebastian, Azoitei, Ninel, Lechel, André, Liebau, Stefan, Wagner, Martin, Simeone, Diane M., Kestler, Hans A., Seufferlein, Thomas, Wiesmüller, Lisa, Rad, Roland, Frappart, Pierre-Olivier, Kleger, Alexander, German Cancer Aid, German Research Foundation, Ulm University, Ministry for Science and Culture of Lower Saxony, Deutsche Krebshilfe, Gout, Johann, Perkhofer, Lukas, Morawe, Mareen, Arnold, Frank, Ihle, Michaela, Biber, Stephanie, Lange, Sebastian, Roger, Elodie, Kraus, Johann M., Stifter, Katja, Hahn, Stephan A., Zamperone, Andrea, Engleitner, Thomas, Müller, Martin, Walter, Karolin, Rodriguez-Aznar, Eva, Sainz, Bruno Jr., Hermann, Patrick C., Hessmann, Elisabeth, Müller, Sebastian, Azoitei, Ninel, Lechel, André, Liebau, Stefan, Wagner, Martin, Simeone, Diane M., Kestler, Hans A., Seufferlein, Thomas, Wiesmüller, Lisa, Rad, Roland, Frappart, Pierre-Olivier, and Kleger, Alexander
Abstract: [Objective]: ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC)., [Design]: Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy., [Results]: Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance., [Conclusion]: Analysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition.
Published: 2020

6. DCG++: A data-driven metric for geometric pattern recognition.

Author: Guan, Jiahui, Kestler, Hans A1, Guan, Jiahui, Hsieh, Fushing, Koehl, Patrice, Guan, Jiahui, Kestler, Hans A1, Guan, Jiahui, Hsieh, Fushing, and Koehl, Patrice
Abstract: Clustering large and complex data sets whose partitions may adopt arbitrary shapes remains a difficult challenge. Part of this challenge comes from the difficulty in defining a similarity measure between the data points that captures the underlying geometry of those data points. In this paper, we propose an algorithm, DCG++ that generates such a similarity measure that is data-driven and ultrametric. DCG++ uses Markov Chain Random Walks to capture the intrinsic geometry of data, scans possible scales, and combines all this information using a simple procedure that is shown to generate an ultrametric. We validate the effectiveness of this similarity measure within the context of clustering on synthetic data with complex geometry, on a real-world data set containing segmented audio records of frog calls described by mel-frequency cepstral coefficients, as well as on an image segmentation problem. The experimental results show a significant improvement on performance with the DCG-based ultrametric compared to using an empirical distance measure.
Published: 2019

7. Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling

Author: Seyfried, Felix, Demir, Salih, Hörl, Rebecca Louise, Stirnweiß, Felix Uli, Ryan, Jeremy; https://orcid.org/0000-0002-3327-1283, Scheffold, Annika, Villalobos-Ortiz, Mariana, Boldrin, Elena, Zinngrebe, Julia, Enzenmüller, Stefanie, Jenni, Silvia, Tsai, Yi-Chien, Bornhauser, Beat, Fürstberger, Axel, Kraus, Johann Michael, Kestler, Hans Armin, Bourquin, Jean-Pierre, Stilgenbauer, Stephan, Letai, Anthony, Debatin, Klaus-Michael, Meyer, Lüder Hinrich, Seyfried, Felix, Demir, Salih, Hörl, Rebecca Louise, Stirnweiß, Felix Uli, Ryan, Jeremy; https://orcid.org/0000-0002-3327-1283, Scheffold, Annika, Villalobos-Ortiz, Mariana, Boldrin, Elena, Zinngrebe, Julia, Enzenmüller, Stefanie, Jenni, Silvia, Tsai, Yi-Chien, Bornhauser, Beat, Fürstberger, Axel, Kraus, Johann Michael, Kestler, Hans Armin, Bourquin, Jean-Pierre, Stilgenbauer, Stephan, Letai, Anthony, Debatin, Klaus-Michael, and Meyer, Lüder Hinrich
Abstract: Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients. Here, we investigated the activity of the BCL-2 inhibitor venetoclax (VEN, ABT-199) in B-cell precursor acute lymphoblastic leukemia and found heterogeneous sensitivities in BCP-ALL cell lines and in a series of patient-derived primografts. To identify parameters of sensitivity and resistance, we evaluated genetic aberrations, gene-expression profiles, expression levels of apoptosis regulators, and functional apoptosis parameters analyzed by mitochondrial profiling using recombinant BH3-like peptides. Importantly, ex vivo VEN sensitivity was most accurately associated with functional BCL-2 dependence detected by BH3 profiling. Modeling clinical application of VEN in a preclinical trial in a set of individual ALL primografts, we identified that leukemia-free survival of VEN treated mice was precisely determined by functional BCL-2 dependence. Moreover, the predictive value of ex vivo measured functional BCL-2 dependence for preclinical in vivo VEN response was confirmed in an independent set of primograft ALL including T- and high risk-ALL. Thus, integrative analysis of the apoptosis signaling indicating mitochondrial addiction to BCL-2 accurately predicts antileukemia activity of VEN, robustly identifies VEN-responsive patients, and provides informati
Published: 2019

8. Patterns of antibody responses to nonviral cancer antigens in head and neck squamous cell carcinoma patients differ by human papillomavirus status

Author: Gangkofner, Dominik S, Holzinger, Dana, Schroeder, Lea, Eichmüller, Stefan B, Zörnig, Inka, Jäger, Dirk, Wichmann, Gunnar; https://orcid.org/0000-0001-6191-2095, Dietz, Andreas, Broglie, Martina A, Herold‐Mende, Christel, Dyckhoff, Gerhard, Boscolo‐Rizzo, Paolo, Ezic, Jasmin, Marienfeld, Ralf B, Möller, Peter, Völkel, Gunnar, Kraus, Johann M, Kestler, Hans A, Brunner, Cornelia; https://orcid.org/0000-0002-6456-5508, Schuler, Patrick J; https://orcid.org/0000-0002-1065-8709, Wigand, Marlene, Theodoraki, Marie N, Doescher, Johannes, Hoffmann, Thomas K, Pawlita, Michael, Butt, Julia, Waterboer, Tim, Laban, Simon; https://orcid.org/0000-0001-6732-7137, Gangkofner, Dominik S, Holzinger, Dana, Schroeder, Lea, Eichmüller, Stefan B, Zörnig, Inka, Jäger, Dirk, Wichmann, Gunnar; https://orcid.org/0000-0001-6191-2095, Dietz, Andreas, Broglie, Martina A, Herold‐Mende, Christel, Dyckhoff, Gerhard, Boscolo‐Rizzo, Paolo, Ezic, Jasmin, Marienfeld, Ralf B, Möller, Peter, Völkel, Gunnar, Kraus, Johann M, Kestler, Hans A, Brunner, Cornelia; https://orcid.org/0000-0002-6456-5508, Schuler, Patrick J; https://orcid.org/0000-0002-1065-8709, Wigand, Marlene, Theodoraki, Marie N, Doescher, Johannes, Hoffmann, Thomas K, Pawlita, Michael, Butt, Julia, Waterboer, Tim, and Laban, Simon; https://orcid.org/0000-0001-6732-7137
Abstract: There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)‐positive and HPV‐negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue‐saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV‐positive and HPV‐negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer‐testis antigens, 5 cancer‐retina antigens and 8 oncogenes) and 29 HPV‐antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV‐positive and 209 HPV‐negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c‐myc, LAGE‐1, MAGE‐A1, ‐A3, ‐A4, NY‐ESO‐1, SpanX‐a1 and p53. AR to MAGE‐A3, MAGE‐A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ≤10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue‐sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV‐positive and HPV‐negative HNSCC.
Published: 2019

9. Antibody responses to cancer antigens identify patients with a poor prognosis among HPV-positive and HPV-negative head and neck squamous cell carcinoma patients

Author: Laban, Simon, Gangkofner, Dominik S, Holzinger, Dana; https://orcid.org/0000-0002-5010-5236, Schroeder, Lea, Eichmüller, Stefan B; https://orcid.org/0000-0002-3497-6904, Zörnig, Inka, Jäger, Dirk, Wichmann, Gunnar, Dietz, Andreas, Broglie, Martina A, Herold-Mende, Christel C, Dyckhoff, Gerhard, Boscolo-Rizzo, Paolo; https://orcid.org/0000-0002-4635-7959, Ezić, Jasmin, Marienfeld, Ralf, Möller, Peter, Kraus, Johann M, Völkel, Gunnar, Kestler, Hans A; https://orcid.org/0000-0002-4759-5254, Brunner, Cornelia; https://orcid.org/0000-0002-6456-5508, Schuler, Patrick J, Wigand, Marlene C, Theodoraki, Marie-Nicole, Doescher, Johannes, Hoffmann, Thomas K, Pawlita, Michael; https://orcid.org/0000-0002-4720-8306, Waterboer, Tim, Butt, Julia; https://orcid.org/0000-0001-7738-8611, Laban, Simon, Gangkofner, Dominik S, Holzinger, Dana; https://orcid.org/0000-0002-5010-5236, Schroeder, Lea, Eichmüller, Stefan B; https://orcid.org/0000-0002-3497-6904, Zörnig, Inka, Jäger, Dirk, Wichmann, Gunnar, Dietz, Andreas, Broglie, Martina A, Herold-Mende, Christel C, Dyckhoff, Gerhard, Boscolo-Rizzo, Paolo; https://orcid.org/0000-0002-4635-7959, Ezić, Jasmin, Marienfeld, Ralf, Möller, Peter, Kraus, Johann M, Völkel, Gunnar, Kestler, Hans A; https://orcid.org/0000-0002-4759-5254, Brunner, Cornelia; https://orcid.org/0000-0002-6456-5508, Schuler, Patrick J, Wigand, Marlene C, Theodoraki, Marie-Nicole, Doescher, Johannes, Hoffmann, Thomas K, Pawlita, Michael; https://orcid.org/0000-0002-4720-8306, Waterboer, Tim, and Butt, Julia; https://orcid.org/0000-0001-7738-8611
Abstract: Purpose: The identification of high-risk patients within Human Papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma patients is needed for improved treatment and surveillance strategies. In this study, we set out to discover Antibody responses (AR) with prognostic impact in head and neck squamous cell carcinoma (HNSCC) stratified by HPV-status. Experimental Design: A fluorescent bead-based multiplex serology assay to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens, 8 oncogenes) and 29 HPV-antigens was performed in samples of 362 HNSCC patients from five independent cohorts (153 HPV-positive, 209 HPV-negative). A multivariable cox proportional hazard model with bootstrapping (M=1000) was used for validation of prognostic antibody responses. Results: AR to any of the cancer antigens were found in 257/362 patients (71%). In HPV-negative patients, antibody responses to to c-myc, MAGE-A1, -A4 and Rhodopsin E2 (combined as ARhigh risk) were significantly associated with shorter overall survival. In HPV-positive patients antibody responses to IMP-1 were discovered as a negative prognostic factor. ARhigh risk (HR=1.76) and antibody responses to IMP-1 (HR=3.28) were confirmed as independent markers for a poor prognosis in a multivariable Cox proportional hazard model with bootstrapping (M=1000). Conclusion: We identified AR to cancer antigens that associate with a dismal prognosis in HNSCC patients beyond HPV-positive-status. ARhigh risk may be used to detect HPV-negative patients with an extraordinarily bad prognosis. Most importantly, AR to IMP-1 may serve as a marker for a subgroup of HPV-positive patients that present with a poor prognosis similar to that in HPV-negative patients.
Published: 2019

10. Representing Dynamic Biological Networks With Multi-Scale Probabilistic Models

Author: Groß, Alexander, Kracher, Barbara, Kraus, Johann M., Kühlwein, Silke D., Pfister, Astrid S., Wiese, Sebastian, Luckert, Katrin, Pötz, Oliver, Joos, Thomas, Van Daele, Dries, De Raedt, Luc, Kühl, Michael, Kestler, Hans A., Groß, Alexander, Kracher, Barbara, Kraus, Johann M., Kühlwein, Silke D., Pfister, Astrid S., Wiese, Sebastian, Luckert, Katrin, Pötz, Oliver, Joos, Thomas, Van Daele, Dries, De Raedt, Luc, Kühl, Michael, and Kestler, Hans A.
Abstract: Dynamic models analyzing gene regulation and metabolism face challenges when adapted to modeling signal transduction networks. During signal transduction, molecular reactions and mechanisms occur in different spatial and temporal frames and involve feedbacks. This impedes the straight-forward use of methods based on Boolean networks, Bayesian approaches, and differential equations. We propose a new approach, ProbRules, that combines probabilities and logical rules to represent the dynamics of a system across multiple scales. We demonstrate that ProbRules models can represent various network motifs of biological systems. As an example of a comprehensive model of signal transduction, we provide a Wnt network that shows remarkable robustness under a range of phenotypical and pathological conditions. Its simulation allows the clarification of controversially discussed molecular mechanisms of Wnt signaling by predicting wet-lab measurements. ProbRules provides an avenue in current computational modeling by enabling systems biologists to integrate vast amounts of available data on different scales.
Published: 2019
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11. Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

Author: Kustermann, Monika, Manta, Linda, Paone, Christoph, Kustermann, Jochen, Lausser, Ludwig, Wiesner, Cora, Eichinger, Ludwig, Clemen, Christoph S., Schroeder, Rolf, Kestler, Hans A., Sandri, Marco, Rottbauer, Wolfgang, Just, Steffen, Kustermann, Monika, Manta, Linda, Paone, Christoph, Kustermann, Jochen, Lausser, Ludwig, Wiesner, Cora, Eichinger, Ludwig, Clemen, Christoph S., Schroeder, Rolf, Kestler, Hans A., Sandri, Marco, Rottbauer, Wolfgang, and Just, Steffen
Abstract: VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells.
Published: 2018

12. Loss of the novel Vcp (valosin containing protein) interactor Washc4 interferes with autophagy-mediated proteostasis in striated muscle and leads to myopathy in vivo

Author: Kustermann, Monika, Manta, Linda, Paone, Christoph, Kustermann, Jochen, Lausser, Ludwig, Wiesner, Cora, Eichinger, Ludwig, Clemen, Christoph S., Schroeder, Rolf, Kestler, Hans A., Sandri, Marco, Rottbauer, Wolfgang, Just, Steffen, Kustermann, Monika, Manta, Linda, Paone, Christoph, Kustermann, Jochen, Lausser, Ludwig, Wiesner, Cora, Eichinger, Ludwig, Clemen, Christoph S., Schroeder, Rolf, Kestler, Hans A., Sandri, Marco, Rottbauer, Wolfgang, and Just, Steffen
Abstract: VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We found that targeted inactivation of either Vcp or Washc4, led to progressive impairment of cardiac and skeletal muscle function, structure and cytoarchitecture without interfering with the differentiation of both organ systems. Notably, loss of Vcp resulted in compromised protein degradation via the proteasome and the macroautophagy/autophagy machinery, whereas Washc4 deficiency did not affect the function of the ubiquitin-proteasome system (UPS) but caused ER stress and interfered with autophagy function in vivo. In summary, our findings provide novel insights into the in vivo functions of Vcp and its novel interactor Washc4 and their particular and distinct roles during proteostasis in striated muscle cells.
Published: 2018

13. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Scott, Robert A., Scott, Laura J., Maegi, Reedik, Marullo, Letizia, Gaulton, Kyle J., Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H., Johnson, Andrew D., Eicher, John D., Jackson, Anne U., Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R., Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F., Grallert, Harald, Mueller-Nurasyid, Martina, Ried, Janina S., Rayner, Nigel W., Robertson, Neil, Karssen, Lennart C., Van Leeuwen, Elisabeth M., Willems, Sara M., Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M., Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A., Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Franberg, Mattias, Strawbridge, Rona J., Benediktsson, Rafn, Hreidarsson, Astradur B., Kong, Augustine, Sigurdsson, Gunnar, Kerrison, Nicola D., Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tonu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J., Pankow, James S., Grarup, Niels, Have, Christian T., Jorgensen, Marit E., Jorgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C., Van Dam, Rob M., Hunter, David J., Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R., Perry, John R. B., Wood, Andrew R., Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R., Bonnycastle, Lori L., Chines, Peter S., Stringham, Heather M., Koistinen, Heikki A., Kinnunen, Leena, Sennblad, Bengt, Muehleisen, Thomas W., Noethen, Markus M., Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E., Tremoli, Elena, Klopp, Norman, Meyer, Julia, Steinbach, Gerald, Wennauer, Roman, Eriksson, Johan G., Mannisto, Satu, Peltonen, Leena, Tikkanen, Emmi, Charpentier, Guillaume, Eury, Elodie, Lobbens, Stephane, Gigante, Bruna, Leander, Karin, McLeod, Olga, Bottinger, Erwin P., Gottesman, Omri, Ruderfer, Douglas, Blueher, Matthias, Kovacs, Peter, Tonjes, Anke, Maruthur, Nisa M., Scapoli, Chiara, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, De Faire, Ulf, Hamsten, Anders, Stumvoll, Michael, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Ripatti, Samuli, Salomaa, Veikko, Pedersen, Nancy L., Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Hansen, Torben, Pedersen, Oluf, Barroso, Ines, Lannfelt, Lars, Ingelsson, Erik, Lind, Lars, Lindgren, Cecilia M., Cauchi, Stephane, Froguel, Philippe, Loos, Ruth J. F., Balkau, Beverley, Boeing, Heiner, Franks, Paul W., Gurrea, Aurelio Barricarte, Palli, Domenico, Van der Schouw, Yvonne T., Altshuler, David, Groop, Leif C., Langenberg, Claudia, Wareham, Nicholas J., Sijbrands, Eric, Van Duijn, Cornelia M., Florez, Jose C., Meigs, James B., Boerwinkle, Eric, Gieger, Christian, Strauch, Konstantin, Metspalu, Andres, Morris, Andrew D., Palmer, Colin N. A., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Dupuis, Josee, Morris, Andrew P., Boehnke, Michael, McCarthy, Mark I., Prokopenko, Inga, Scott, Robert A., Scott, Laura J., Maegi, Reedik, Marullo, Letizia, Gaulton, Kyle J., Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H., Johnson, Andrew D., Eicher, John D., Jackson, Anne U., Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R., Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F., Grallert, Harald, Mueller-Nurasyid, Martina, Ried, Janina S., Rayner, Nigel W., Robertson, Neil, Karssen, Lennart C., Van Leeuwen, Elisabeth M., Willems, Sara M., Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M., Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A., Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Franberg, Mattias, Strawbridge, Rona J., Benediktsson, Rafn, Hreidarsson, Astradur B., Kong, Augustine, Sigurdsson, Gunnar, Kerrison, Nicola D., Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tonu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J., Pankow, James S., Grarup, Niels, Have, Christian T., Jorgensen, Marit E., Jorgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C., Van Dam, Rob M., Hunter, David J., Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R., Perry, John R. B., Wood, Andrew R., Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R., Bonnycastle, Lori L., Chines, Peter S., Stringham, Heather M., Koistinen, Heikki A., Kinnunen, Leena, Sennblad, Bengt, Muehleisen, Thomas W., Noethen, Markus M., Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E., Tremoli, Elena, Klopp, Norman, Meyer, Julia, Steinbach, Gerald, Wennauer, Roman, Eriksson, Johan G., Mannisto, Satu, Peltonen, Leena, Tikkanen, Emmi, Charpentier, Guillaume, Eury, Elodie, Lobbens, Stephane, Gigante, Bruna, Leander, Karin, McLeod, Olga, Bottinger, Erwin P., Gottesman, Omri, Ruderfer, Douglas, Blueher, Matthias, Kovacs, Peter, Tonjes, Anke, Maruthur, Nisa M., Scapoli, Chiara, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, De Faire, Ulf, Hamsten, Anders, Stumvoll, Michael, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Ripatti, Samuli, Salomaa, Veikko, Pedersen, Nancy L., Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Hansen, Torben, Pedersen, Oluf, Barroso, Ines, Lannfelt, Lars, Ingelsson, Erik, Lind, Lars, Lindgren, Cecilia M., Cauchi, Stephane, Froguel, Philippe, Loos, Ruth J. F., Balkau, Beverley, Boeing, Heiner, Franks, Paul W., Gurrea, Aurelio Barricarte, Palli, Domenico, Van der Schouw, Yvonne T., Altshuler, David, Groop, Leif C., Langenberg, Claudia, Wareham, Nicholas J., Sijbrands, Eric, Van Duijn, Cornelia M., Florez, Jose C., Meigs, James B., Boerwinkle, Eric, Gieger, Christian, Strauch, Konstantin, Metspalu, Andres, Morris, Andrew D., Palmer, Colin N. A., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Dupuis, Josee, Morris, Andrew P., Boehnke, Michael, McCarthy, Mark I., and Prokopenko, Inga
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Published: 2017
Full Text: View/download PDF

14. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Scott, Robert A., Scott, Laura J., Maegi, Reedik, Marullo, Letizia, Gaulton, Kyle J., Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H., Johnson, Andrew D., Eicher, John D., Jackson, Anne U., Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R., Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F., Grallert, Harald, Mueller-Nurasyid, Martina, Ried, Janina S., Rayner, Nigel W., Robertson, Neil, Karssen, Lennart C., Van Leeuwen, Elisabeth M., Willems, Sara M., Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M., Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A., Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Franberg, Mattias, Strawbridge, Rona J., Benediktsson, Rafn, Hreidarsson, Astradur B., Kong, Augustine, Sigurdsson, Gunnar, Kerrison, Nicola D., Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tonu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J., Pankow, James S., Grarup, Niels, Have, Christian T., Jorgensen, Marit E., Jorgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C., Van Dam, Rob M., Hunter, David J., Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R., Perry, John R. B., Wood, Andrew R., Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R., Bonnycastle, Lori L., Chines, Peter S., Stringham, Heather M., Koistinen, Heikki A., Kinnunen, Leena, Sennblad, Bengt, Muehleisen, Thomas W., Noethen, Markus M., Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E., Tremoli, Elena, Klopp, Norman, Meyer, Julia, Steinbach, Gerald, Wennauer, Roman, Eriksson, Johan G., Mannisto, Satu, Peltonen, Leena, Tikkanen, Emmi, Charpentier, Guillaume, Eury, Elodie, Lobbens, Stephane, Gigante, Bruna, Leander, Karin, McLeod, Olga, Bottinger, Erwin P., Gottesman, Omri, Ruderfer, Douglas, Blueher, Matthias, Kovacs, Peter, Tonjes, Anke, Maruthur, Nisa M., Scapoli, Chiara, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, De Faire, Ulf, Hamsten, Anders, Stumvoll, Michael, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Ripatti, Samuli, Salomaa, Veikko, Pedersen, Nancy L., Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Hansen, Torben, Pedersen, Oluf, Barroso, Ines, Lannfelt, Lars, Ingelsson, Erik, Lind, Lars, Lindgren, Cecilia M., Cauchi, Stephane, Froguel, Philippe, Loos, Ruth J. F., Balkau, Beverley, Boeing, Heiner, Franks, Paul W., Gurrea, Aurelio Barricarte, Palli, Domenico, Van der Schouw, Yvonne T., Altshuler, David, Groop, Leif C., Langenberg, Claudia, Wareham, Nicholas J., Sijbrands, Eric, Van Duijn, Cornelia M., Florez, Jose C., Meigs, James B., Boerwinkle, Eric, Gieger, Christian, Strauch, Konstantin, Metspalu, Andres, Morris, Andrew D., Palmer, Colin N. A., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Dupuis, Josee, Morris, Andrew P., Boehnke, Michael, McCarthy, Mark I., Prokopenko, Inga, Scott, Robert A., Scott, Laura J., Maegi, Reedik, Marullo, Letizia, Gaulton, Kyle J., Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H., Johnson, Andrew D., Eicher, John D., Jackson, Anne U., Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R., Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F., Grallert, Harald, Mueller-Nurasyid, Martina, Ried, Janina S., Rayner, Nigel W., Robertson, Neil, Karssen, Lennart C., Van Leeuwen, Elisabeth M., Willems, Sara M., Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M., Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A., Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Franberg, Mattias, Strawbridge, Rona J., Benediktsson, Rafn, Hreidarsson, Astradur B., Kong, Augustine, Sigurdsson, Gunnar, Kerrison, Nicola D., Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tonu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J., Pankow, James S., Grarup, Niels, Have, Christian T., Jorgensen, Marit E., Jorgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C., Van Dam, Rob M., Hunter, David J., Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R., Perry, John R. B., Wood, Andrew R., Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R., Bonnycastle, Lori L., Chines, Peter S., Stringham, Heather M., Koistinen, Heikki A., Kinnunen, Leena, Sennblad, Bengt, Muehleisen, Thomas W., Noethen, Markus M., Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E., Tremoli, Elena, Klopp, Norman, Meyer, Julia, Steinbach, Gerald, Wennauer, Roman, Eriksson, Johan G., Mannisto, Satu, Peltonen, Leena, Tikkanen, Emmi, Charpentier, Guillaume, Eury, Elodie, Lobbens, Stephane, Gigante, Bruna, Leander, Karin, McLeod, Olga, Bottinger, Erwin P., Gottesman, Omri, Ruderfer, Douglas, Blueher, Matthias, Kovacs, Peter, Tonjes, Anke, Maruthur, Nisa M., Scapoli, Chiara, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, De Faire, Ulf, Hamsten, Anders, Stumvoll, Michael, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Ripatti, Samuli, Salomaa, Veikko, Pedersen, Nancy L., Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Hansen, Torben, Pedersen, Oluf, Barroso, Ines, Lannfelt, Lars, Ingelsson, Erik, Lind, Lars, Lindgren, Cecilia M., Cauchi, Stephane, Froguel, Philippe, Loos, Ruth J. F., Balkau, Beverley, Boeing, Heiner, Franks, Paul W., Gurrea, Aurelio Barricarte, Palli, Domenico, Van der Schouw, Yvonne T., Altshuler, David, Groop, Leif C., Langenberg, Claudia, Wareham, Nicholas J., Sijbrands, Eric, Van Duijn, Cornelia M., Florez, Jose C., Meigs, James B., Boerwinkle, Eric, Gieger, Christian, Strauch, Konstantin, Metspalu, Andres, Morris, Andrew D., Palmer, Colin N. A., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Dupuis, Josee, Morris, Andrew P., Boehnke, Michael, McCarthy, Mark I., and Prokopenko, Inga
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Published: 2017
Full Text: View/download PDF

15. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2017

16. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2017

17. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2017

18. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Scott, Robert A., Scott, Laura J., Maegi, Reedik, Marullo, Letizia, Gaulton, Kyle J., Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H., Johnson, Andrew D., Eicher, John D., Jackson, Anne U., Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R., Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F., Grallert, Harald, Mueller-Nurasyid, Martina, Ried, Janina S., Rayner, Nigel W., Robertson, Neil, Karssen, Lennart C., Van Leeuwen, Elisabeth M., Willems, Sara M., Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M., Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A., Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J., Benediktsson, Rafn, Hreidarsson, Astradur B., Kong, Augustine, Sigurdsson, Gunnar, Kerrison, Nicola D., Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tonu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J., Pankow, James S., Grarup, Niels, Have, Christian T., Jorgensen, Marit E., Jorgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C., Van Dam, Rob M., Hunter, David J., Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R., Perry, John R. B., Wood, Andrew R., Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R., Bonnycastle, Lori L., Chines, Peter S., Stringham, Heather M., Koistinen, Heikki A., Kinnunen, Leena, Sennblad, Bengt, Muehleisen, Thomas W., Noethen, Markus M., Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E., Tremoli, Elena, Klopp, Norman, Meyer, Julia, Steinbach, Gerald, Wennauer, Roman, Eriksson, Johan G., Mannisto, Satu, Peltonen, Leena, Tikkanen, Emmi, Charpentier, Guillaume, Eury, Elodie, Lobbens, Stephane, Gigante, Bruna, Leander, Karin, McLeod, Olga, Bottinger, Erwin P., Gottesman, Omri, Ruderfer, Douglas, Blueher, Matthias, Kovacs, Peter, Tonjes, Anke, Maruthur, Nisa M., Scapoli, Chiara, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, De Faire, Ulf, Hamsten, Anders, Stumvoll, Michael, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Ripatti, Samuli, Salomaa, Veikko, Pedersen, Nancy L., Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Hansen, Torben, Pedersen, Oluf, Barroso, Ines, Lannfelt, Lars, Ingelsson, Erik, Lind, Lars, Lindgren, Cecilia M., Cauchi, Stephane, Froguel, Philippe, Loos, Ruth J. F., Balkau, Beverley, Boeing, Heiner, Franks, Paul W., Gurrea, Aurelio Barricarte, Palli, Domenico, Van der Schouw, Yvonne T., Altshuler, David, Groop, Leif C., Langenberg, Claudia, Wareham, Nicholas J., Sijbrands, Eric, Van Duijn, Cornelia M., Florez, Jose C., Meigs, James B., Boerwinkle, Eric, Gieger, Christian, Strauch, Konstantin, Metspalu, Andres, Morris, Andrew D., Palmer, Colin N. A., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Dupuis, Josee, Morris, Andrew P., Boehnke, Michael, McCarthy, Mark I., Prokopenko, Inga, Scott, Robert A., Scott, Laura J., Maegi, Reedik, Marullo, Letizia, Gaulton, Kyle J., Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H., Johnson, Andrew D., Eicher, John D., Jackson, Anne U., Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R., Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F., Grallert, Harald, Mueller-Nurasyid, Martina, Ried, Janina S., Rayner, Nigel W., Robertson, Neil, Karssen, Lennart C., Van Leeuwen, Elisabeth M., Willems, Sara M., Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M., Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A., Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J., Benediktsson, Rafn, Hreidarsson, Astradur B., Kong, Augustine, Sigurdsson, Gunnar, Kerrison, Nicola D., Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tonu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J., Pankow, James S., Grarup, Niels, Have, Christian T., Jorgensen, Marit E., Jorgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C., Van Dam, Rob M., Hunter, David J., Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R., Perry, John R. B., Wood, Andrew R., Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R., Bonnycastle, Lori L., Chines, Peter S., Stringham, Heather M., Koistinen, Heikki A., Kinnunen, Leena, Sennblad, Bengt, Muehleisen, Thomas W., Noethen, Markus M., Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E., Tremoli, Elena, Klopp, Norman, Meyer, Julia, Steinbach, Gerald, Wennauer, Roman, Eriksson, Johan G., Mannisto, Satu, Peltonen, Leena, Tikkanen, Emmi, Charpentier, Guillaume, Eury, Elodie, Lobbens, Stephane, Gigante, Bruna, Leander, Karin, McLeod, Olga, Bottinger, Erwin P., Gottesman, Omri, Ruderfer, Douglas, Blueher, Matthias, Kovacs, Peter, Tonjes, Anke, Maruthur, Nisa M., Scapoli, Chiara, Erbel, Raimund, Joeckel, Karl-Heinz, Moebus, Susanne, De Faire, Ulf, Hamsten, Anders, Stumvoll, Michael, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., Ripatti, Samuli, Salomaa, Veikko, Pedersen, Nancy L., Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Tuomilehto, Jaakko, Hansen, Torben, Pedersen, Oluf, Barroso, Ines, Lannfelt, Lars, Ingelsson, Erik, Lind, Lars, Lindgren, Cecilia M., Cauchi, Stephane, Froguel, Philippe, Loos, Ruth J. F., Balkau, Beverley, Boeing, Heiner, Franks, Paul W., Gurrea, Aurelio Barricarte, Palli, Domenico, Van der Schouw, Yvonne T., Altshuler, David, Groop, Leif C., Langenberg, Claudia, Wareham, Nicholas J., Sijbrands, Eric, Van Duijn, Cornelia M., Florez, Jose C., Meigs, James B., Boerwinkle, Eric, Gieger, Christian, Strauch, Konstantin, Metspalu, Andres, Morris, Andrew D., Palmer, Colin N. A., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Dupuis, Josee, Morris, Andrew P., Boehnke, Michael, McCarthy, Mark I., and Prokopenko, Inga
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Published: 2017
Full Text: View/download PDF

19. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

Author: Scott, Robert A, Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, Nigel W, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, Kong, Augustine, Sigurðsson, Gunnar, Kerrison, Nicola D, Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tõnu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J, Pankow, James S, Grarup, Niels, Have, Christian T, Jørgensen, Marit E, Jørgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C, van Dam, Rob M, Hunter, David J, Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R, Perry, John RB, Wood, Andrew R, Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R, Bonnycastle, Lori L, Chines, Peter S, Stringham, Heather M, Koistinen, Heikki A, Kinnunen, Leena, Sennblad, Bengt, Mühleisen, Thomas W, Nöthen, Markus M, Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E, Tremoli, Elena, Klopp, Norman, Meyer, Julia, Steinbach, Gerald, Scott, Robert A, Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, Nigel W, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, Kong, Augustine, Sigurðsson, Gunnar, Kerrison, Nicola D, Luan, Jian'an, Liang, Liming, Meitinger, Thomas, Roden, Michael, Thorand, Barbara, Esko, Tõnu, Mihailov, Evelin, Fox, Caroline, Liu, Ching-Ti, Rybin, Denis, Isomaa, Bo, Lyssenko, Valeriya, Tuomi, Tiinamaija, Couper, David J, Pankow, James S, Grarup, Niels, Have, Christian T, Jørgensen, Marit E, Jørgensen, Torben, Linneberg, Allan, Cornelis, Marilyn C, van Dam, Rob M, Hunter, David J, Kraft, Peter, Sun, Qi, Edkins, Sarah, Owen, Katharine R, Perry, John RB, Wood, Andrew R, Zeggini, Eleftheria, Tajes-Fernandes, Juan, Abecasis, Goncalo R, Bonnycastle, Lori L, Chines, Peter S, Stringham, Heather M, Koistinen, Heikki A, Kinnunen, Leena, Sennblad, Bengt, Mühleisen, Thomas W, Nöthen, Markus M, Pechlivanis, Sonali, Baldassarre, Damiano, Gertow, Karl, Humphries, Steve E, Tremoli, Elena, Klopp, Norman, Meyer, Julia, and Steinbach, Gerald
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
Published: 2017

20. An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

Author: Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Epidemiology & Health Economics, Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Epidemiology & Health Economics, Scott, Robert A, Scott, Laura J, Mägi, Reedik, Marullo, Letizia, Gaulton, Kyle J, Kaakinen, Marika, Pervjakova, Natalia, Pers, Tune H, Johnson, Andrew D, Eicher, John D, Jackson, Anne U, Ferreira, Teresa, Lee, Yeji, Ma, Clement, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Van Zuydam, Natalie R, Mahajan, Anubha, Chen, Han, Almgren, Peter, Voight, Ben F, Grallert, Harald, Müller-Nurasyid, Martina, Ried, Janina S, Rayner, William N, Robertson, Neil, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Fuchsberger, Christian, Kwan, Phoenix, Teslovich, Tanya M, Chanda, Pritam, Li, Man, Lu, Yingchang, Dina, Christian, Thuillier, Dorothee, Yengo, Loic, Jiang, Longda, Sparso, Thomas, Kestler, Hans A, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Frånberg, Mattias, Strawbridge, Rona J, Benediktsson, Rafn, Hreidarsson, Astradur B, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2017

21. Cooperative development of logical modelling standards and tools with CoLoMoTo

Author: Naldi, Aurélien, Monteiro, Pedro T., Müssel, Christoph, Kestler, Hans A., Thieffry, Denis, Xenarios, Ioannis, Saez-Rodriguez, Julio, Helikar, Tomas, Chaouiya, Claudine, Naldi, Aurélien, Monteiro, Pedro T., Müssel, Christoph, Kestler, Hans A., Thieffry, Denis, Xenarios, Ioannis, Saez-Rodriguez, Julio, Helikar, Tomas, and Chaouiya, Claudine
Abstract: The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the logical modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in logical modelling or in related mathematical and computational developments. Contact: contact@colomoto.org
Published: 2017

22. Analysis of Large and Complex Data

Author: Wilhelm, Adalbert F.X. editor., Kestler, Hans A. editor., SpringerLink (Online service), Wilhelm, Adalbert F.X. editor., Kestler, Hans A. editor., and SpringerLink (Online service)
Abstract: This book offers a snapshot of the state-of-the-art in classification at the interface between statistics, computer science and application fields. The contributions span a broad spectrum, from theoretical developments to practical applications; they all share a strong computational component. The topics addressed are from the following fields: Statistics and Data Analysis; Machine Learning and Knowledge Discovery; Data Analysis in Marketing; Data Analysis in Finance and Economics; Data Analysis in Medicine and the Life Sciences; Data Analysis in the Social, Behavioural, and Health Care Sciences; Data Analysis in Interdisciplinary Domains; Classification and Subject Indexing in Library and Information Science. The book presents selected papers from the Second European Conference on Data Analysis, held at Jacobs University Bremen in July 2014. This conference unites diverse researchers in the pursuit of a common topic, creating truly unique synergies in the process.p>.
Published: 2016

23. Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma

Author: Dahlhaus, Meike, Burkovski, Andre, Hertwig, Falk, Mussel, Christoph, Volland, Ruth, Fischer, Matthias, Debatin, Klaus-Michael, Kestler, Hans A., Beltinger, Christian, Dahlhaus, Meike, Burkovski, Andre, Hertwig, Falk, Mussel, Christoph, Volland, Ruth, Fischer, Matthias, Debatin, Klaus-Michael, Kestler, Hans A., and Beltinger, Christian
Abstract: Aurora Kinase A (AURKA) is often overexpressed in neuroblastoma (NB) with poor outcome. The causes of AURKA overexpression in NB are unknown. Here, we describe a gene regulatory network consisting of core regulators of AURKA protein expression and activation during mitosis to identify potential causes. This network was transformed to a dynamic Boolean model. Simulated activation of the serine/threonine protein kinase Greatwall (GWL, encoded by MASTL) that attenuates the pivotal AURKA inhibitor PP2A, predicted stabilization of AURKA. Consistent with this notion, gene set enrichment analysis showed enrichment of mitotic spindle assembly genes and MYCN target genes in NB with high GWL/MASTL expression. In line with the prediction of GWL/MASTL enhancing AURKA, elevated expression of GWL/MASTL was associated with NB risk factors and poor survival of patients. These results establish Boolean network modeling of oncogenic pathways in NB as a useful means for guided discovery in this enigmatic cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
Published: 2016

24. Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma

Author: Dahlhaus, Meike, Burkovski, Andre, Hertwig, Falk, Mussel, Christoph, Volland, Ruth, Fischer, Matthias, Debatin, Klaus-Michael, Kestler, Hans A., Beltinger, Christian, Dahlhaus, Meike, Burkovski, Andre, Hertwig, Falk, Mussel, Christoph, Volland, Ruth, Fischer, Matthias, Debatin, Klaus-Michael, Kestler, Hans A., and Beltinger, Christian
Abstract: Aurora Kinase A (AURKA) is often overexpressed in neuroblastoma (NB) with poor outcome. The causes of AURKA overexpression in NB are unknown. Here, we describe a gene regulatory network consisting of core regulators of AURKA protein expression and activation during mitosis to identify potential causes. This network was transformed to a dynamic Boolean model. Simulated activation of the serine/threonine protein kinase Greatwall (GWL, encoded by MASTL) that attenuates the pivotal AURKA inhibitor PP2A, predicted stabilization of AURKA. Consistent with this notion, gene set enrichment analysis showed enrichment of mitotic spindle assembly genes and MYCN target genes in NB with high GWL/MASTL expression. In line with the prediction of GWL/MASTL enhancing AURKA, elevated expression of GWL/MASTL was associated with NB risk factors and poor survival of patients. These results establish Boolean network modeling of oncogenic pathways in NB as a useful means for guided discovery in this enigmatic cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
Published: 2016

25. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Franberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., Morris, Andrew P., Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Franberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., and Morris, Andrew P.
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Published: 2015
Full Text: View/download PDF

26. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Franberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., Morris, Andrew P., Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Franberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., and Morris, Andrew P.
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Published: 2015
Full Text: View/download PDF

27. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Author: Gaulton, Kyle J, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, Rayner, N William, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B, Grarup, Niels, Groves, Christopher J, Hassinen, Maija, Have, Christian T, Herder, Christian, Holmen, Oddgeir L, Hreidarsson, Astradur B, Humphries, Steve E, Hunter, David J, Jackson, Anne U, Jonsson, Anna, Jørgensen, Marit E, Jørgensen, Torben, Kao, Wen-Hong L, Kerrison, Nicola D, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Gaulton, Kyle J, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, Rayner, N William, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B, Grarup, Niels, Groves, Christopher J, Hassinen, Maija, Have, Christian T, Herder, Christian, Holmen, Oddgeir L, Hreidarsson, Astradur B, Humphries, Steve E, Hunter, David J, Jackson, Anne U, Jonsson, Anna, Jørgensen, Marit E, Jørgensen, Torben, Kao, Wen-Hong L, Kerrison, Nicola D, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, and Langford, Cordelia
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Published: 2015

28. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2015

29. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., Morris, Andrew P., Gaulton, Kyle J., Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Maegi, Reedik, Reschen, Michael E., Mahajan, Anubha, Locke, Adam, Rayner, N. William, Robertson, Neil, Scott, Robert A., Prokopenko, Inga, Scott, Laura J., Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J., Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C., van Leeuwen, Elisabeth M., Willems, Sara M., Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K., Rundle, Jana K., Beer, Nicola L., van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F., Abecasis, Goncalo R., Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blueher, Matthias, Boeing, Heiner, Bonnycastle, Lori L., Bottinger, Erwin P., Burtt, Noel P., Carey, Jason, Charpentier, Guillaume, Chines, Peter S., Cornelis, Marilyn C., Couper, David J., Crenshaw, Andrew T., van Dam, Rob M., Doney, Alex S. F., Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G., Esko, Tonu, Eury, Elodie, Fadista, Joao, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W., Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B., Grarup, Niels, Groves, Christopher J., Hassinen, Maija, Have, Christian T., Herder, Christian, Holmen, Oddgeir L., Hreidarsson, Astradur B., Humphries, Steve E., Hunter, David J., Jackson, Anne U., Jonsson, Anna, Jorgensen, Marit E., Jorgensen, Torben, Kao, Wen-Hong L., Kerrison, Nicola D., Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Leander, Karin, Liang, Liming, Lichtner, Peter, Lindgren, Cecilia M., Lindholm, Eero, Linneberg, Allan, Liu, Ching-Ti, Lobbens, Stephane, Luan, Jian'an, Lyssenko, Valeriya, Mannisto, Satu, McLeod, Olga, Meyer, Julia, Mihailov, Evelin, Mirza, Ghazala, Muehleisen, Thomas W., Mueller-Nurasyid, Martina, Navarro, Carmen, Noethen, Markus M., Oskolkov, Nikolay N., Owen, Katharine R., Palli, Domenico, Pechlivanis, Sonali, Peltonen, Leena, Perry, John R. B., Platou, Carl G. P., Roden, Michael, Ruderfer, Douglas, Rybin, Denis, van der Schouw, Yvonne T., Sennblad, Bengt, Sigurdsson, Gunnar, Stancakova, Alena, Steinbach, Gerald, Storm, Petter, Strauch, Konstantin, Stringham, Heather M., Sun, Qi, Thorand, Barbara, Tikkanen, Emmi, Tonjes, Anke, Trakalo, Joseph, Tremoli, Elena, Tuomi, Tiinamaija, Wennauer, Roman, Wiltshire, Steven, Wood, Andrew R., Zeggini, Eleftheria, Dunham, Ian, Birney, Ewan, Pasquali, Lorenzo, Ferrer, Jorge, Loos, Ruth J. F., Dupuis, Josee, Florez, Jose C., Boerwinkle, Eric, Pankow, James S., van Duijn, Cornelia, Sijbrands, Eric, Meigs, James B., Hu, Frank B., Thorsteinsdottir, Unnur, Stefansson, Kari, Lakka, Timo A., Rauramaa, Rainer, Stumvoll, Michael, Pedersen, Nancy L., Lind, Lars, Keinanen-Kiukaanniemi, Sirkka M., Korpi-Hyovalti, Eeva, Saaristo, Timo E., Saltevo, Juha, Kuusisto, Johanna, Laakso, Markku, Metspalu, Andres, Erbel, Raimund, Joecke, Karl-Heinz, Moebus, Susanne, Ripatti, Samuli, Salomaa, Veikko, Ingelsson, Erik, Boehm, Bernhard O., Bergman, Richard N., Collins, Francis S., Mohlke, Karen L., Koistinen, Heikki, Tuomilehto, Jaakko, Hveem, Kristian, Njolstad, Inger, Deloukas, Panagiotis, Donnelly, Peter J., Frayling, Timothy M., Hattersley, Andrew T., de Faire, Ulf, Hamsten, Anders, Illig, Thomas, Peters, Annette, Cauchi, Stephane, Sladek, Rob, Froguel, Philippe, Hansen, Torben, Pedersen, Oluf, Morris, Andrew D., Palmer, Collin N. A., Kathiresan, Sekar, Melander, Olle, Nilsson, Peter M., Groop, Leif C., Barroso, Ines, Langenberg, Claudia, Wareham, Nicholas J., O'Callaghan, Christopher A., Gloyn, Anna L., Altshuler, David, Boehnke, Michael, Teslovich, Tanya M., McCarthy, Mark I., and Morris, Andrew P.
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Published: 2015
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30. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2015

31. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Author: Gaulton, Kyle J, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, Rayner, N William, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B, Grarup, Niels, Groves, Christopher J, Hassinen, Maija, Have, Christian T, Herder, Christian, Holmen, Oddgeir L, Hreidarsson, Astradur B, Humphries, Steve E, Hunter, David J, Jackson, Anne U, Jonsson, Anna, Jørgensen, Marit E, Jørgensen, Torben, Kao, Wen-Hong L, Kerrison, Nicola D, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, Langford, Cordelia, Gaulton, Kyle J, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, Rayner, N William, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, Benediktsson, Rafn, Blüher, Matthias, Boeing, Heiner, Bonnycastle, Lori L, Bottinger, Erwin P, Burtt, Noël P, Carey, Jason, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Doney, Alex SF, Dorkhan, Mozhgan, Edkins, Sarah, Eriksson, Johan G, Esko, Tonu, Eury, Elodie, Fadista, João, Flannick, Jason, Fontanillas, Pierre, Fox, Caroline, Franks, Paul W, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Gottesman, Omri, Grant, George B, Grarup, Niels, Groves, Christopher J, Hassinen, Maija, Have, Christian T, Herder, Christian, Holmen, Oddgeir L, Hreidarsson, Astradur B, Humphries, Steve E, Hunter, David J, Jackson, Anne U, Jonsson, Anna, Jørgensen, Marit E, Jørgensen, Torben, Kao, Wen-Hong L, Kerrison, Nicola D, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Kovacs, Peter, Kraft, Peter, Kravic, Jasmina, and Langford, Cordelia
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Published: 2015

32. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2015

33. The association of statin use after cancer diagnosis with survival in pancreatic cancer patients: a SEER-medicare analysis.

Author: Jeon, Christie Y, Kestler, Hans A1, Jeon, Christie Y, Pandol, Stephen J, Wu, Bechien, Cook-Wiens, Galen, Gottlieb, Roberta A, Merz, C Noel Bairey, Goodman, Marc T, Jeon, Christie Y, Kestler, Hans A1, Jeon, Christie Y, Pandol, Stephen J, Wu, Bechien, Cook-Wiens, Galen, Gottlieb, Roberta A, Merz, C Noel Bairey, and Goodman, Marc T
Abstract: BackgroundPancreatic cancer has poor prognosis and existing interventions provide a modest benefit. Statin has anti-cancer properties that might enhance survival in pancreatic cancer patients. We sought to determine whether statin treatment after cancer diagnosis is associated with longer survival in those with pancreatic ductal adenocarcinoma (PDAC).MethodsWe analyzed data on 7813 elderly patients with PDAC using the linked Surveillance, Epidemiology, and End Results (SEER) - Medicare claims files. Information on the type, intensity and duration of statin use after cancer diagnosis was extracted from Medicare Part D. We treated statin as a time-dependent variable in a Cox regression model to determine the association with overall survival adjusting for follow-up, age, sex, race, neighborhood income, stage, grade, tumor size, pancreatectomy, chemotherapy, radiation, obesity, dyslipidemia, diabetes, chronic pancreatitis and chronic obstructive pulmonary disease (COPD).ResultsOverall, statin use after cancer diagnosis was not significantly associated with survival when all PDAC patients were considered (HR = 0.94, 95%CI 0.89, 1.01). However, statin use after cancer diagnosis was associated with a 21% reduced hazard of death (Hazard ratio = 0.79, 95% confidence interval (CI) 0.67, 0.93) in those with grade I or II PDAC and to a similar extent in those who had undergone a pancreatectomy, in those with chronic pancreatitis and in those who had not been treated with statin prior to cancer diagnosis.ConclusionsWe found that statin treatment after cancer diagnosis is associated with enhanced survival in patients with low-grade, resectable PDAC.
Published: 2015

34. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epidemiologie, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Circulatory Health, Cardiovasculaire Epidemiologie, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Beer, Nicola L, van de Bunt, Martijn, Chalisey, Anil, Kang, Hyun Min, Voight, Benjamin F, Abecasis, Gonçalo R, Almgren, Peter, Baldassarre, Damiano, Balkau, Beverley, van der Schouw, Yvonne T, and DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium
Published: 2015

35. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Grarup, Niels, Have, Christian T, Jonsson, Anna, Jørgensen, Marit Eika, Jørgensen, Torben, Linneberg, Allan, Storm, Petter, Njølstad, Inger, Hansen, Torben, Pedersen, Oluf, Gaulton, Kyle J, Ferreira, Teresa, Lee, Yeji, Raimondo, Anne, Mägi, Reedik, Reschen, Michael E, Mahajan, Anubha, Locke, Adam, William Rayner, N, Robertson, Neil, Scott, Robert A, Prokopenko, Inga, Scott, Laura J, Green, Todd, Sparso, Thomas, Thuillier, Dorothee, Yengo, Loic, Grallert, Harald, Wahl, Simone, Frånberg, Mattias, Strawbridge, Rona J, Kestler, Hans, Chheda, Himanshu, Eisele, Lewin, Gustafsson, Stefan, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Qi, Lu, Karssen, Lennart C, van Leeuwen, Elisabeth M, Willems, Sara M, Li, Man, Chen, Han, Fuchsberger, Christian, Kwan, Phoenix, Ma, Clement, Linderman, Michael, Lu, Yingchang, Thomsen, Soren K, Rundle, Jana K, Grarup, Niels, Have, Christian T, Jonsson, Anna, Jørgensen, Marit Eika, Jørgensen, Torben, Linneberg, Allan, Storm, Petter, Njølstad, Inger, Hansen, Torben, and Pedersen, Oluf
Abstract: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Published: 2015

36. Assessment of Automated Analyses of Cell Migration on Flat and Nanostructured Surfaces

Author: Gradinaru, Cristian, Lopacinska, Joanna M., Huth, Johannes, Kestler, Hans A., Flyvbjerg, Henrik, Mølhave, Kristian, Gradinaru, Cristian, Lopacinska, Joanna M., Huth, Johannes, Kestler, Hans A., Flyvbjerg, Henrik, and Mølhave, Kristian
Abstract: Motility studies of cells often rely on computer software that analyzes time-lapse recorded movies and establishes cell trajectories fully automatically. This raises the question of reproducibility of results, since different programs could yield significantly different results of such automated analysis. The fact that the segmentation routines of such programs are often challenged by nanostructured surfaces makes the question more pertinent. Here we illustrate how it is possible to track cells on bright field microscopy images with image analysis routines implemented in an open-source cell tracking program, PACT (Program for Automated Cell Tracking). We compare the automated motility analysis of three cell tracking programs, PACT, Autozell, and TLA, using the same movies as input for all three programs. We find that different programs track overlapping, but different subsets of cells due to different segmentation methods. Unfortunately, population averages based on such different cell populations, differ significantly in some cases. Thus, results obtained with one software package are not necessarily reproducible by other software.
Published: 2012

37. Assessment of Automated Analyses of Cell Migration on Flat and Nanostructured Surfaces

Author: Gradinaru, Cristian, Lopacinska, Joanna M., Huth, Johannes, Kestler, Hans A., Flyvbjerg, Henrik, Mølhave, Kristian, Gradinaru, Cristian, Lopacinska, Joanna M., Huth, Johannes, Kestler, Hans A., Flyvbjerg, Henrik, and Mølhave, Kristian
Abstract: Motility studies of cells often rely on computer software that analyzes time-lapse recorded movies and establishes cell trajectories fully automatically. This raises the question of reproducibility of results, since different programs could yield significantly different results of such automated analysis. The fact that the segmentation routines of such programs are often challenged by nanostructured surfaces makes the question more pertinent. Here we illustrate how it is possible to track cells on bright field microscopy images with image analysis routines implemented in an open-source cell tracking program, PACT (Program for Automated Cell Tracking). We compare the automated motility analysis of three cell tracking programs, PACT, Autozell, and TLA, using the same movies as input for all three programs. We find that different programs track overlapping, but different subsets of cells due to different segmentation methods. Unfortunately, population averages based on such different cell populations, differ significantly in some cases. Thus, results obtained with one software package are not necessarily reproducible by other software.
Published: 2012

38. Assessment of Automated Analyses of Cell Migration on Flat and Nanostructured Surfaces

Author: Gradinaru, Cristian, Lopacinska, Joanna M., Huth, Johannes, Kestler, Hans A., Flyvbjerg, Henrik, Mølhave, Kristian, Gradinaru, Cristian, Lopacinska, Joanna M., Huth, Johannes, Kestler, Hans A., Flyvbjerg, Henrik, and Mølhave, Kristian
Abstract: Motility studies of cells often rely on computer software that analyzes time-lapse recorded movies and establishes cell trajectories fully automatically. This raises the question of reproducibility of results, since different programs could yield significantly different results of such automated analysis. The fact that the segmentation routines of such programs are often challenged by nanostructured surfaces makes the question more pertinent. Here we illustrate how it is possible to track cells on bright field microscopy images with image analysis routines implemented in an open-source cell tracking program, PACT (Program for Automated Cell Tracking). We compare the automated motility analysis of three cell tracking programs, PACT, Autozell, and TLA, using the same movies as input for all three programs. We find that different programs track overlapping, but different subsets of cells due to different segmentation methods. Unfortunately, population averages based on such different cell populations, differ significantly in some cases. Thus, results obtained with one software package are not necessarily reproducible by other software.
Published: 2012

39. TimeLapseAnalyzer: Multi-target analysis for live-cell imaging and time-lapse microscopy

Author: Huth, Johannes, Buchholz, Malte, Kraus, Johann M., Mølhave, Kristian, Gradinaru, Cristian, v. Wichert, Götz, Gress, Thomas M., Neumann, Heiko, Kestler, Hans A., Huth, Johannes, Buchholz, Malte, Kraus, Johann M., Mølhave, Kristian, Gradinaru, Cristian, v. Wichert, Götz, Gress, Thomas M., Neumann, Heiko, and Kestler, Hans A.
Abstract: The direct observation of cells over time using time-lapse microscopy can provide deep insights into many important biological processes. Reliable analyses of motility, proliferation, invasive potential or mortality of cells are essential to many studies involving live cell imaging and can aid in biomarker discovery and diagnostic decisions. Given the vast amount of image- and time-series data produced by modern microscopes, automated analysis is a key feature to capitalize the potential of time-lapse imaging devices. To provide fast and reproducible analyses of multiple aspects of cell behaviour, we developed TimeLapseAnalyzer. Apart from general purpose image enhancements and segmentation procedures, this extensible, self-contained, modular cross-platform package provides dedicated modalities for fast and reliable analysis of multi-target cell tracking, scratch wound healing analysis, cell counting and tube formation analysis in high throughput screening of live-cell experiments. TimeLapseAnalyzer is freely available (MATLAB, Open Source) at http://www.informatik.uniulm. de/ni/mitarbeiter/HKestler/tla.
Published: 2011

40. Chromosomal Integration of Adenoviral Vector DNA In Vivo

Author: Stephen, Sam Laurel, Montini, Eugenio, Sivanandam, Vijayshankar Ganesh, Al-Dhalimy, Muhseen, Kestler, Hans A., Finegold, Milton, Grompe, Markus, Kochanek, Stefan, Stephen, Sam Laurel, Montini, Eugenio, Sivanandam, Vijayshankar Ganesh, Al-Dhalimy, Muhseen, Kestler, Hans A., Finegold, Milton, Grompe, Markus, and Kochanek, Stefan
Abstract: So far there has been no report of any clinical or preclinical evidence for chromosomal vector integration following adenovirus (Ad) vector-mediated gene transfer in vivo. We used liver gene transfer with high-capacity Ad vectors in the FAH(Delta exon5) mouse model to analyze homologous and heterologous recombination events between vector and chromosomal DNA. Intravenous injection of Ad vectors either expressing a fumarylacetoacetate hydrolase (FAH) cDNA or carrying part of the FAH genomic locus resulted in liver nodules of FAH-expressing hepatocytes, demonstrating chromosomal vector integration. Analysis of junctions between vector and chromosomal DNA following heterologous recombination indicated integration of the vector genome through its termini. Heterologous recombination occurred with a median frequency of 6.72 x 10(-5) per transduced hepatocyte, while homologous recombination occurred more rarely with a median frequency of 3.88 x 10(-7). This study has established quantitative and qualitative data on recombination of adenoviral vector DNA with genomic DNA in vivo, contributing to a risk-benefit assessment of the biosafety of Ad vector-mediated gene transfer.
Published: 2010

41. Chromosomal Integration of Adenoviral Vector DNA In Vivo

Author: Stephen, Sam Laurel, Montini, Eugenio, Sivanandam, Vijayshankar Ganesh, Al-Dhalimy, Muhseen, Kestler, Hans A., Finegold, Milton, Grompe, Markus, Kochanek, Stefan, Stephen, Sam Laurel, Montini, Eugenio, Sivanandam, Vijayshankar Ganesh, Al-Dhalimy, Muhseen, Kestler, Hans A., Finegold, Milton, Grompe, Markus, and Kochanek, Stefan
Abstract: So far there has been no report of any clinical or preclinical evidence for chromosomal vector integration following adenovirus (Ad) vector-mediated gene transfer in vivo. We used liver gene transfer with high-capacity Ad vectors in the FAH(Delta exon5) mouse model to analyze homologous and heterologous recombination events between vector and chromosomal DNA. Intravenous injection of Ad vectors either expressing a fumarylacetoacetate hydrolase (FAH) cDNA or carrying part of the FAH genomic locus resulted in liver nodules of FAH-expressing hepatocytes, demonstrating chromosomal vector integration. Analysis of junctions between vector and chromosomal DNA following heterologous recombination indicated integration of the vector genome through its termini. Heterologous recombination occurred with a median frequency of 6.72 x 10(-5) per transduced hepatocyte, while homologous recombination occurred more rarely with a median frequency of 3.88 x 10(-7). This study has established quantitative and qualitative data on recombination of adenoviral vector DNA with genomic DNA in vivo, contributing to a risk-benefit assessment of the biosafety of Ad vector-mediated gene transfer.
Published: 2010

42. Cooperative development of logical modelling standards and tools with CoLoMoTo

Author: Naldi, Aurélien, Monteiro, Pedro T., Müssel, Christoph, Kestler, Hans A., Thieffry, Denis, Xenarios, Ioannis, Saez-Rodriguez, Julio, Helikar, Tomas, Chaouiya, Claudine, Naldi, Aurélien, Monteiro, Pedro T., Müssel, Christoph, Kestler, Hans A., Thieffry, Denis, Xenarios, Ioannis, Saez-Rodriguez, Julio, Helikar, Tomas, and Chaouiya, Claudine
Abstract: The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the logical modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in logical modelling or in related mathematical and computational developments. Contact: contact@colomoto.org

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