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44 results on '"Aparna, Radhakrishnan"'

1. The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities

Author

Eric Venner, Karynne Patterson, Divya Kalra, Marsha M. Wheeler, Yi-Ju Chen, Sara E. Kalla, Bo Yuan, Jason H. Karnes, Kimberly Walker, Joshua D. Smith, Sean McGee, Aparna Radhakrishnan, Andrew Haddad, Philip E. Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail Jarvik, Anjene Musick, Richard A. Gibbs, and the All of Us Research Program Investigators

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Disparities in data underlying clinical genomic interpretation is an acknowledged problem, but there is a paucity of data demonstrating it. The All of Us Research Program is collecting data including whole-genome sequences, health records, and surveys for at least a million participants with diverse ancestry and access to healthcare, representing one of the largest biomedical research repositories of its kind. Here, we examine pathogenic and likely pathogenic variants that were identified in the All of Us cohort. The European ancestry subgroup showed the highest overall rate of pathogenic variation, with 2.26% of participants having a pathogenic variant. Other ancestry groups had lower rates of pathogenic variation, including 1.62% for the African ancestry group and 1.32% in the Latino/Admixed American ancestry group. Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer or Hypercholesterolemia. Variant frequencies in many genes were consistent with the data from the public gnomAD database, with some notable exceptions resolved using gnomAD subsets. Differences in pathogenic variant frequency observed between ancestral groups generally indicate biases of ascertainment of knowledge about those variants, but some deviations may be indicative of differences in disease prevalence. This work will allow targeted precision medicine efforts at revealed disparities.

Published
2024
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2. Author Correction: The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities

Author

Eric Venner, Karynne Patterson, Divya Kalra, Marsha M. Wheeler, Yi-Ju Chen, Sara E. Kalla, Bo Yuan, Jason H. Karnes, Kimberly Walker, Joshua D. Smith, Sean McGee, Aparna Radhakrishnan, Andrew Haddad, Philip E. Empey, Qiaoyan Wang, Lee Lichtenstein, Diana Toledo, Gail Jarvik, Anjene Musick, Richard A. Gibbs, and on behalf of the All of Us Research Program Investigators

Subjects
Biology (General), QH301-705.5
Published
2024
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3. Implementation of FAIR principles in the IPCC: the WGI AR6 Atlas repository

Author

Maialen Iturbide, Jesús Fernández, José M. Gutiérrez, Anna Pirani, David Huard, Alaa Al Khourdajie, Jorge Baño-Medina, Joaquin Bedia, Ana Casanueva, Ezequiel Cimadevilla, Antonio S. Cofiño, Matteo De Felice, Javier Diez-Sierra, Markel García-Díez, James Goldie, Dimitris A. Herrera, Sixto Herrera, Rodrigo Manzanas, Josipa Milovac, Aparna Radhakrishnan, Daniel San-Martín, Alessandro Spinuso, Kristen M. Thyng, Claire Trenham, and Özge Yelekçi

Subjects
Science
Abstract

Abstract The Sixth Assessment Report (AR6) of the Intergovernmental Panel on Climate Change (IPCC) has adopted the FAIR Guiding Principles. We present the Atlas chapter of Working Group I (WGI) as a test case. We describe the application of the FAIR principles in the Atlas, the challenges faced during its implementation, and those that remain for the future. We introduce the open source repository resulting from this process, including coding (e.g., annotated Jupyter notebooks), data provenance, and some aggregated datasets used in some figures in the Atlas chapter and its interactive companion (the Interactive Atlas), open to scrutiny by the scientific community and the general public. We describe the informal pilot review conducted on this repository to gather recommendations that led to significant improvements. Finally, a working example illustrates the re-use of the repository resources to produce customized regional information, extending the Interactive Atlas products and running the code interactively in a web browser using Jupyter notebooks.

Published
2022
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4. Digital competence of higher education learners in the context of COVID-19 triggered online learning

Author

Sreeram Vishnu, Archana Raghavan Sathyan, Anu Susan Sam, Aparna Radhakrishnan, Sulaja Olaparambil Ragavan, Jasna Vattam Kandathil, and Christoph Funk

Subjects
Competence, Learning management system, Pandemic, Lock-down, Digital divide, History of scholarship and learning. The humanities, AZ20-999, Social sciences (General), H1-99
Abstract

The spread of COVID-19 caused wide scale disruptions in the educational sector across the globe. Digital education, which involves the use of digital tools, virtual platforms and online learning, is seen as one of the viable alternatives to continue academic activities in such an environment. Higher education institutions have largely switched to this new mode of learning and continue to rely on digital mode in many parts of the world, due to the ongoing pandemic threat. However, learners' competency to effectively engage in online courses and the impact of their socioeconomic background on this competency has not been adequately addressed in the literature. The present study was an attempt to explore these aspects, as they are crucial to the success of digital education. The study was conducted with 833 undergraduate, postgraduate, and doctoral students from an agricultural university to assess their digital competencies and factors that influence effective participation in online courses. The Digital Competence Framework 2.0 of EU Science Hub (DIGCOMP) was adapted and used for this study. Our findings suggest that the learners have a satisfactory level of competence in most of the aspects of digital competence. Majority of the participants were relying on smart phones both as the device for accessing internet as well as for their learning activities. The results of a Tukey's difference in the mean test reveals that learners' digital competence varies significantly by gender, economic profile, and academic level. This finding can be attributed to the difference in their socio-economic background, which confirms digital divide among learners. Our findings have implications for the design of digital higher education strategies and institutional management to ensure effective learner participation, especially for higher education institutions in developing countries.

Published
2022
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5. The GFDL Global Ocean and Sea Ice Model OM4.0: Model Description and Simulation Features

Author

Alistair Adcroft, Whit Anderson, V. Balaji, Chris Blanton, Mitchell Bushuk, Carolina O. Dufour, John P. Dunne, Stephen M. Griffies, Robert Hallberg, Matthew J. Harrison, Isaac M. Held, Malte F. Jansen, Jasmin G. John, John P. Krasting, Amy R. Langenhorst, Sonya Legg, Zhi Liang, Colleen McHugh, Aparna Radhakrishnan, Brandon G. Reichl, Tony Rosati, Bonita L. Samuels, Andrew Shao, Ronald Stouffer, Michael Winton, Andrew T. Wittenberg, Baoqiang Xiang, Niki Zadeh, and Rong Zhang

Subjects
ocean circulation model, CORE, hybrid coordinates, Physical geography, GB3-5030, Oceanography, GC1-1581
Abstract

Abstract We document the configuration and emergent simulation features from the Geophysical Fluid Dynamics Laboratory (GFDL) OM4.0 ocean/sea ice model. OM4 serves as the ocean/sea ice component for the GFDL climate and Earth system models. It is also used for climate science research and is contributing to the Coupled Model Intercomparison Project version 6 Ocean Model Intercomparison Project. The ocean component of OM4 uses version 6 of the Modular Ocean Model and the sea ice component uses version 2 of the Sea Ice Simulator, which have identical horizontal grid layouts (Arakawa C‐grid). We follow the Coordinated Ocean‐sea ice Reference Experiments protocol to assess simulation quality across a broad suite of climate‐relevant features. We present results from two versions differing by horizontal grid spacing and physical parameterizations: OM4p5 has nominal 0.5° spacing and includes mesoscale eddy parameterizations and OM4p25 has nominal 0.25° spacing with no mesoscale eddy parameterization. Modular Ocean Model version 6 makes use of a vertical Lagrangian‐remap algorithm that enables general vertical coordinates. We show that use of a hybrid depth‐isopycnal coordinate reduces the middepth ocean warming drift commonly found in pure z* vertical coordinate ocean models. To test the need for the mesoscale eddy parameterization used in OM4p5, we examine the results from a simulation that removes the eddy parameterization. The water mass structure and model drift are physically degraded relative to OM4p5, thus supporting the key role for a mesoscale closure at this resolution.

Published
2019
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7. Meiotic Interactors of a Mitotic Gene TAO3 Revealed by Functional Analysis of its Rare Variant

Author

Saumya Gupta, Aparna Radhakrishnan, Rachana Nitin, Pandu Raharja-Liu, Gen Lin, Lars M. Steinmetz, Julien Gagneur, and Himanshu Sinha

Subjects
rare variant, TAO3, meiosis, transcriptome profiling, allelic variant, Genetics, QH426-470
Abstract

Studying the molecular consequences of rare genetic variants has the potential to identify novel and hitherto uncharacterized pathways causally contributing to phenotypic variation. Here, we characterize the functional consequences of a rare coding variant of TAO3, previously reported to contribute significantly to sporulation efficiency variation in Saccharomyces cerevisiae. During mitosis, the common TAO3 allele interacts with CBK1—a conserved NDR kinase. Both TAO3 and CBK1 are components of the RAM signaling network that regulates cell separation and polarization during mitosis. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2—a RAM network target gene. By quantitatively measuring cell morphological dynamics, and expressing the TAO3(4477C) allele conditionally during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation identified regulators of carbon and lipid metabolic pathways as candidate mediators. We show experimentally that, during sporulation, the TAO3(4477C) allele interacts genetically with ERT1 and PIP2, regulators of the tricarboxylic acid cycle and gluconeogenesis metabolic pathways, respectively. We thus uncover a meiotic functional role for TAO3, and identify ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that studying the causal effects of genetic variation on the underlying molecular network has the potential to provide a more extensive understanding of the pathways driving a complex trait.

Published
2016
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8. Centers for Mendelian Genomics: A decade of facilitating gene discovery

Author

Samantha M. Baxter, Jennifer E. Posey, Nicole J. Lake, Nara Sobreira, Jessica X. Chong, Steven Buyske, Elizabeth E. Blue, Lisa H. Chadwick, Zeynep H. Coban-Akdemir, Kimberly F. Doheny, Colleen P. Davis, Monkol Lek, Christopher Wellington, Shalini N. Jhangiani, Mark Gerstein, Richard A. Gibbs, Richard P. Lifton, Daniel G. MacArthur, Tara C. Matise, James R. Lupski, David Valle, Michael J. Bamshad, Ada Hamosh, Shrikant Mane, Deborah A. Nickerson, Heidi L. Rehm, Anne O’Donnell-Luria, Marcia Adams, François Aguet, Gulsen Akay, Peter Anderson, Corina Antonescu, Harindra M. Arachchi, Mehmed M. Atik, Christina A. Austin-Tse, Larry Babb, Tamara J. Bacus, Vahid Bahrambeigi, Suganthi Balasubramanian, Yavuz Bayram, Arthur L. Beaudet, Christine R. Beck, John W. Belmont, Jennifer E. Below, Kaya Bilguvar, Corinne D. Boehm, Eric Boerwinkle, Philip M. Boone, Sara J. Bowne, Harrison Brand, Kati J. Buckingham, Alicia B. Byrne, Daniel Calame, Ian M. Campbell, Xiaolong Cao, Claudia Carvalho, Varuna Chander, Jaime Chang, Katherine R. Chao, Ivan K. Chinn, Declan Clarke, Ryan L. Collins, Beryl Cummings, Zain Dardas, Moez Dawood, Kayla Delano, Stephanie P. DiTroia, Harshavardhan Doddapaneni, Haowei Du, Renqian Du, Ruizhi Duan, Mohammad Eldomery, Christine M. Eng, Eleina England, Emily Evangelista, Selin Everett, Jawid Fatih, Adam Felsenfeld, Laurent C. Francioli, Christian D. Frazar, Jack Fu, Emmanuel Gamarra, Tomasz Gambin, Weiniu Gan, Mira Gandhi, Vijay S. Ganesh, Kiran V. Garimella, Laura D. Gauthier, Danielle Giroux, Claudia Gonzaga-Jauregui, Julia K. Goodrich, William W. Gordon, Sean Griffith, Christopher M. Grochowski, Shen Gu, Sanna Gudmundsson, Stacey J. Hall, Adam Hansen, Tamar Harel, Arif O. Harmanci, Isabella Herman, Kurt Hetrick, Hadia Hijazi, Martha Horike-Pyne, Elvin Hsu, Jianhong Hu, Yongqing Huang, Jameson R. Hurless, Steve Jahl, Gail P. Jarvik, Yunyun Jiang, Eric Johanson, Angad Jolly, Ender Karaca, Michael Khayat, James Knight, J. Thomas Kolar, Sushant Kumar, Seema Lalani, Kristen M. Laricchia, Kathryn E. Larkin, Suzanne M. Leal, Gabrielle Lemire, Richard A. Lewis, He Li, Hua Ling, Rachel B. Lipson, Pengfei Liu, Alysia Kern Lovgren, Francesc López-Giráldez, Melissa P. MacMillan, Brian E. Mangilog, Stacy Mano, Dana Marafi, Beth Marosy, Jamie L. Marshall, Renan Martin, Colby T. Marvin, Michelle Mawhinney, Sean McGee, Daniel J. McGoldrick, Michelle Mehaffey, Betselote Mekonnen, Xiaolu Meng, Tadahiro Mitani, Christina Y. Miyake, David Mohr, Shaine Morris, Thomas E. Mullen, David R. Murdock, Mullai Murugan, Donna M. Muzny, Ben Myers, Juanita Neira, Kevin K. Nguyen, Patrick M. Nielsen, Natalie Nudelman, Emily O’Heir, Melanie C. O’Leary, Chrissie Ongaco, Jordan Orange, Ikeoluwa A. Osei-Owusu, Ingrid S. Paine, Lynn S. Pais, Justin Paschall, Karynne Patterson, Davut Pehlivan, Benjamin Pelle, Samantha Penney, Jorge Perez de Acha Chavez, Emma Pierce-Hoffman, Cecilia M. Poli, Jaya Punetha, Aparna Radhakrishnan, Matthew A. Richardson, Eliete Rodrigues, Gwendolin T. Roote, Jill A. Rosenfeld, Erica L. Ryke, Aniko Sabo, Alice Sanchez, Isabelle Schrauwen, Daryl A. Scott, Fritz Sedlazeck, Jillian Serrano, Chad A. Shaw, Tameka Shelford, Kathryn M. Shively, Moriel Singer-Berk, Joshua D. Smith, Hana Snow, Grace Snyder, Matthew Solomonson, Rachel G. Son, Xiaofei Song, Pawel Stankiewicz, Taylorlyn Stephan, V. Reid Sutton, Abigail Sveden, Diana Cornejo Sánchez, Monica Tackett, Michael Talkowski, Machiko S. Threlkeld, Grace Tiao, Miriam S. Udler, Laura Vail, Zaheer Valivullah, Elise Valkanas, Grace E. VanNoy, Qingbo S. Wang, Gao Wang, Lu Wang, Michael F. Wangler, Nicholas A. Watts, Ben Weisburd, Jeffrey M. Weiss, Marsha M. Wheeler, Janson J. White, Clara E. Williamson, Michael W. Wilson, Wojciech Wiszniewski, Marjorie A. Withers, Dane Witmer, Lauren Witzgall, Elizabeth Wohler, Monica H. Wojcik, Isaac Wong, Jordan C. Wood, Nan Wu, Jinchuan Xing, Yaping Yang, Qian Yi, Bo Yuan, Jordan E. Zeiger, Chaofan Zhang, Peng Zhang, Yan Zhang, Xiaohong Zhang, Yeting Zhang, Shifa Zhang, Huda Zoghbi, and Igna van den Veyver

Subjects
Phenotype, Exome Sequencing, Humans, Exome, Genomics, Article, Genetic Association Studies, Genetics (clinical)
Abstract

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

Published
2022
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9. CYP2C8, CYP2C9, and CYP2C19 Characterization Using Next-Generation Sequencing and Haplotype Analysis

Author

Andrea Gaedigk, Erin C. Boone, Steven E. Scherer, Seung-been Lee, Ibrahim Numanagić, Cenk Sahinalp, Joshua D. Smith, Sean McGee, Aparna Radhakrishnan, Xiang Qin, Wendy Y. Wang, Emily G. Farrow, Nina Gonzaludo, Aaron L. Halpern, Deborah A. Nickerson, Neil A. Miller, Victoria M. Pratt, and Lisa V. Kalman

Subjects
Molecular Medicine, Pathology and Forensic Medicine
Published
2022
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10. Process-oriented diagnostics: principles, practice, community development and common standards

Author

J. David Neelin, John P. Krasting, Aparna Radhakrishnan, Jessica Liptak, Thomas Jackson, Yi Ming, Wenhao Dong, Andrew Gettelman, Danielle R. Coleman, Eric D. Maloney, Allison A. Wing, Yi-Hung Kuo, Fiaz Ahmed, Paul Ullrich, Cecilia M. Bitz, Richard B. Neale, Ana Ordonez, and Elizabeth A. Maroon

Subjects
Atmospheric Science
Abstract

Process-oriented diagnostics (PODs) aim to provide feedback for model developers through model analysis based on physical hypotheses. However, the step from a diagnostic based on relationships among variables, even when hypothesis-driven, to specific guidance for revising model formulation or parameterizations can be substantial. The POD may provide more information than a purely performance-based metric, but a gap between POD principles and providing actionable information for specific model revisions can remain. Furthermore, in coordinating diagnostics development, there is a trade-off between freedom for the developer, aiming to capture innovation, and near-term utility to the modeling center. Best practices that allow for the former, while conforming to specifications that aid the latter, are important for community diagnostics development that leads to tangible model improvements. Promising directions to close the gap between principles and practice include the interaction of PODs with perturbed physics experiments and with more quantitative process models as well as the inclusion of personnel from modeling centers in diagnostics development groups for immediate feedback during climate model revisions. Examples are provided, along with best-practice recommendations, based on practical experience from the NOAA Model Diagnostics Task Force (MDTF). Common standards for metrics and diagnostics that have arisen from a collaboration between the MDTF and the Department of Energy’s Coordinated Model Evaluation Capability are advocated as a means of uniting community diagnostics efforts.

Published
2023
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11. Harmonizing variant classification for return of results in the All of Us Research Program

Author

Steven M. Harrison, Christina A. Austin‐Tse, Serra Kim, Matthew Lebo, Annette Leon, David Murdock, Aparna Radhakrishnan, Brian H. Shirts, Marcie Steeves, Eric Venner, Richard A. Gibbs, Gail P. Jarvik, and Heidi L. Rehm

Subjects
Population Health, Genome, Human, Genetics, Genetic Variation, Humans, Genetic Testing, Genomics, United States, Genetics (clinical)
Abstract

The All of Us Research Program (AoURP) is a historic effort to accelerate research and improve healthcare by generating and collating data from one million people in the United States. Participants will have the option to receive results from their genome analysis, including actionable findings in 59 gene-disorder pairs for which disorder-associated variants are recommended for return by the American College of Medical Genetics and Genomics. To ensure consistent reporting across the AoURP, in a prelaunch study the four participating clinical laboratories shared all variant classifications in the 59 genes of interest from their internal databases. Of the 11,813 unique variants classified by at least two of the four laboratories, classifications were concordant with regard to reportability for 99.1% (11,711), with only 0.9% (102) having reportability differences. Through variant reassessment, data sharing, and discussion of rationale, participating laboratories resolved all 102 reportable differences. These approaches will be maintained during routine AoU reporting to ensure continuous classification harmonization and consistent reporting within AoURP.

Published
2021
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12. The frequency of pathogenic variation in the All of Us cohort reveals ancestry-driven disparities

Author

Eric Venner, Karynne Patterson, Divya Kalra, Marsha M. Wheeler, Yi-Ju Chen, Sara E. Kalla, Bo Yuan, Jason H. Karnes, Breanna Lee, Kimberly Walker, Josh Smith, Sean Mcgee, Aparna Radhakrishnan, Andrew Haddad, Qiaoyan Wang, Gail Jarvik, Diana Toledo, Anjene Musick, and Richard A. Gibbs

Abstract

Disparities in the data that underlies clinical genomic interpretation is an acknowledged problem but there is a paucity of data demonstrating it. The National Institutes of Health’sAll of UsResearch Program aims to collect whole genome sequences, electronic health record (EHR) data, surveys and physical measurements for over a million participants of diverse ancestry and varied access to healthcare resources. We grouped participants by computed genetic ancestry and summarized the frequency of pathogenic variation within these groups. The European subgroup showed the highest rate of pathogenic variation (2.1%), with other ancestry groups ranging from 1.04% (East Asian) to 1.87% (‘Other’). Pathogenic variants were most frequently observed in genes related to Breast/Ovarian Cancer, Hypercholesterolemia or Hemochromatosis. Variant frequencies were consistent with gnomAD and some notable exceptions were resolved using gnomAD subsets. We additionally use this data to enrich sets of participants for specific genetic findings and to calculate penetrance. Differences in the frequency of pathogenic variants observed between ancestral groups generally indicate biases of ascertainment, but some may indicate differences in disease prevalence. These analyses are available on theAll of UsResearcher Workbench.

Published
2022
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14. SNP in human ARHGEF3 promoter is associated with DNase hypersensitivity, transcript level and platelet function, and Arhgef3 KO mice have increased mean platelet volume.

Author

Siying Zou, Alexandra M Teixeira, Myrto Kostadima, William J Astle, Aparna Radhakrishnan, Lukas Mikolaj Simon, Lucy Truman, Jennifer S Fang, John Hwa, Ping-Xia Zhang, Pim van der Harst, Paul F Bray, Willem H Ouwehand, Mattia Frontini, and Diane S Krause

Subjects
Medicine, Science
Abstract

Genome-wide association studies have identified a genetic variant at 3p14.3 (SNP rs1354034) that strongly associates with platelet number and mean platelet volume in humans. While originally proposed to be intronic, analysis of mRNA expression in primary human hematopoietic subpopulations reveals that this SNP is located directly upstream of the predominantly expressed ARHGEF3 isoform in megakaryocytes (MK). We found that ARHGEF3, which encodes a Rho guanine exchange factor, is dramatically upregulated during both human and murine MK maturation. We show that the SNP (rs1354034) is located in a DNase I hypersensitive region in human MKs and is an expression quantitative locus (eQTL) associated with ARHGEF3 expression level in human platelets, suggesting that it may be the causal SNP that accounts for the variations observed in human platelet traits and ARHGEF3 expression. In vitro human platelet activation assays revealed that rs1354034 is highly correlated with human platelet activation by ADP. In order to test whether ARHGEF3 plays a role in MK development and/or platelet function, we developed an Arhgef3 KO/LacZ reporter mouse model. Reflecting changes in gene expression, LacZ expression increases during MK maturation in these mice. Although Arhgef3 KO mice have significantly larger platelets, loss of Arhgef3 does not affect baseline MK or platelets nor does it affect platelet function or platelet recovery in response to antibody-mediated platelet depletion compared to littermate controls. In summary, our data suggest that modulation of ARHGEF3 gene expression in humans with a promoter-localized SNP plays a role in human MKs and human platelet function-a finding resulting from the biological follow-up of human genetic studies. Arhgef3 KO mice partially recapitulate the human phenotype.

Published
2017
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15. Comparison of RSM and ANN Optimization Techniques and Modeling of Ultrasonic Energy Assisted Trans-esterification of Salviniaceae Filiculoides Oil Blended to Biodiesel

Author

A. Amala Mithin Minther Singh, P. Arul Franco, Aparna Radhakrishnan, and G. R. Jinu

Subjects
Biodiesel, Materials science, Chemical engineering, biology, Salviniaceae, Materials Chemistry, Ultrasonic sensor, Trans esterification, biology.organism_classification, Energy (signal processing)
Abstract

For the transesterification of biodiesel from Azolla oil, the safe and successful use of feed stocks is a very significant prerequisite. It is of high importance to determine the optimal reaction parameters to maximize the yield of low-cost biodiesel generated from Azolla oil. Ultrasonic energy was used in this work for the development of biodiesel from Azolla oil catalyzed by the KOH catalyst under different conditions. The effect on the transesterification of Azolla Oil to biodiesel of four reaction parameters, namely the methanol/Azolla oil molar ratio (A), KOH catalyst concentration (B), reaction time (C) and reaction temperature (D) were considered. In order to optimize the effects of reaction parameters for the transesterification of Azolla oil to biodiesel, response surface methodology (RSM) based on central composite rotatable design (CCRD) is applied. To obtain a good correlation between the input reaction parameters and the output response parameter (FAME yield) from Azolla oil to biodiesel, an artificial neural network (ANN) model with two feed-forward back-propagation neural-network architecture Multilayer Perceptron Network (MLP) and Radial Basis Function Network (RBFN) was developed. With the experimental information obtained from the RSM model, the built ANN models were trained and evaluated. Absolute Average Deviation (AAD), Root Mean Square Error (RMSE), Mean Absolute Percentage Error (MAPE) and coefficient of determination were statistically compared with the predictive capacity of both RSM and ANN models (R2). The statistical analysis showed that the measured FAME yield from both the RSM and ANN models was able to predict the FAME yield, and the findings limited the ANN model to the much more reliable FAME yield prediction compared to the RSM model.

Published
2021
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17. Factors Influencing the Fish Consumption Preferences: Understandings from the tribes of Wayanad, Kerala

Author

M. V. Sajeev, Aparna Radhakrishnan, C.G. Joshy, R. Gopika, Suseela Mathew, C.N. Ravishankar, A. K. Mohanty, and V. P. Akber Ali

Subjects
Consumption (economics), business.industry, Sardine, food and beverages, Health benefits, Fish consumption, humanities, Geography, Agriculture, Per capita, population characteristics, Health profile, Socioeconomics, business, Socioeconomic status, geographic locations
Abstract

Fish consumption preferences vary with communities. The study aims to study the socio personal and fish consumption profile of the seven major tribes of Wayanad, Kerala. Species preferences, factors affecting the fish purchase and consumption, health profile and symptoms of tribes in relation with iron deficiency anaemia, association between fish consumption and health of tribes were investigated. Data were gathered through a questionnaire completed by 200 tribal households from different socioeconomic backgrounds. Results indicate that Sardine was the most consumed and preferred fish and percapita fish consumption of tribes was far below the state average. In conclusion, the price of fish ranked as the first and foremost important factor affecting the fish purchase and consumption of the tribes surveyed, and the fish consumption variables were highly associated with health values. Increasing awareness about the health benefits of fish consumption and building capacity of tribes to prepare fish-based products based on their taste and preferences can aid improved fish consumption among Wayanad tribes. Therefore, to establish and adopt fish consumption guidelines for the tribes of Wayanad, the factors mentioned in the study need to be integrated into the projects and policies.

Published
2021
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18. The Modular Adaptive Ribosome.

Author

Anupama Yadav, Aparna Radhakrishnan, Anshuman Panda, Amartya Singh, Himanshu Sinha, and Gyan Bhanot

Subjects
Medicine, Science
Abstract

The ribosome is an ancient machine, performing the same function across organisms. Although functionally unitary, recent experiments suggest specialized roles for some ribosomal proteins. Our central thesis is that ribosomal proteins function in a modular fashion to decode genetic information in a context dependent manner. We show through large data analyses that although many ribosomal proteins are essential with consistent effect on growth in different conditions in yeast and similar expression across cell and tissue types in mice and humans, some ribosomal proteins are used in an environment specific manner. The latter set of variable ribosomal proteins further function in a coordinated manner forming modules, which are adapted to different environmental cues in different organisms. We show that these environment specific modules of ribosomal proteins in yeast have differential genetic interactions with other pathways and their 5'UTRs show differential signatures of selection in yeast strains, presumably to facilitate adaptation. Similarly, we show that in higher metazoans such as mice and humans, different modules of ribosomal proteins are expressed in different cell types and tissues. A clear example is nervous tissue that uses a ribosomal protein module distinct from the rest of the tissues in both mice and humans. Our results suggest a novel stratification of ribosomal proteins that could have played a role in adaptation, presumably to optimize translation for adaptation to diverse ecological niches and tissue microenvironments.

Published
2016
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19. Precision medicine for developmental and epileptic encephalopathies in Africa—strategies for a resource-limited setting

Author

Alina I. Esterhuizen, Nicki Tiffin, Gillian Riordan, Marie Wessels, Richard J. Burman, Miriam C. Aziz, Jeffrey D. Calhoun, Jonathan Gunti, Ezra E. Amiri, Aishwarya Ramamurthy, Michael J. Bamshad, Heather C. Mefford, Raj Ramesar, Jo M. Wilmshurst, Gemma L. Carvill, Suzanne M. Leal, Deborah A. Nickerson, Peter Anderson, Tamara J. Bacus, Elizabeth E. Blue, Katherine Brower, Kati J. Buckingham, Jessica X. Chong, Diana Cornejo Sánchez, Colleen P. Davis, Chayna J. Davis, Christian D. Frazar, Katherine Gomeztagle-Burgess, William W. Gordon, Martha Horike-Pyne, Jameson R. Hurless, Gail P. Jarvik, Eric Johanson, J. Thomas Kolar, Colby T. Marvin, Sean McGee, Daniel J. McGoldrick, Betselote Mekonnen, Patrick M. Nielsen, Karynne Patterson, Aparna Radhakrishnan, Matthew A. Richardson, Gwendolin T. Roote, Erica L. Ryke, Isabelle Schrauwen, Kathryn M. Shively, Joshua D. Smith, Monica Tackett, Gao Wang, Jeffrey M. Weiss, Marsha M. Wheeler, Qian Yi, and Xiaohong Zhang

Subjects
Genetics (clinical)
Abstract

Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A presumed proportion is genetic, but this etiology is buried under the burden of infections and perinatal insults in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs) are most severely affected by this diagnostic gap in Africa, because the rate of actionable findings is highest in DEE-associated genes.We tested 234 genetically naive South African children diagnosed with/possible DEE using gene panels, exome sequencing, and chromosomal microarray. Statistical comparison of electroclinical features in children with and children without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding.Of the 41 (of 234) children with likely/pathogenic variants, 26 had variants supporting precision therapy. Multivariate regression modeling highlighted neonatal or infantile-onset seizures and movement abnormalities as predictive of a positive genetic finding. We used this, coupled with an emphasis on precision medicine outcomes, to propose the pragmatic "Think-Genetics" strategy for early recognition of a possible genetic etiology.Our findings emphasize the importance of an early genetic diagnosis in DEE. We designed the Think-Genetics strategy for early recognition, appropriate interim management, and genetic testing for DEE in resource-constrained settings.

Published
2023
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20. Temporal expression profiling identifies pathways mediating effect of causal variant on phenotype.

Author

Saumya Gupta, Aparna Radhakrishnan, Pandu Raharja-Liu, Gen Lin, Lars M Steinmetz, Julien Gagneur, and Himanshu Sinha

Subjects
Genetics, QH426-470
Abstract

Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants' effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression.

Published
2015
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21. The GFDL Global Ocean and Sea Ice Model OM4.0: Model Description and Simulation Features

Author

Aparna Radhakrishnan, Andrew Shao, John P. Krasting, Mitchell Bushuk, Jasmin G. John, Baoqiang Xiang, Isaac M. Held, Brandon G. Reichl, Sonya Legg, Andrew T. Wittenberg, Malte F. Jansen, Venkatramani Balaji, Bonita L. Samuels, Robert Hallberg, Alistair Adcroft, Carolina O. Dufour, Michael Winton, A. R. Langenhorst, Zhi Liang, Chris Blanton, Rong Zhang, John P. Dunne, Niki Zadeh, Tony Rosati, Stephen M. Griffies, Colleen McHugh, Ronald J. Stouffer, Matthew Harrison, and Whit G. Anderson

Subjects
010504 meteorology & atmospheric sciences, Carbon mitigation, 01 natural sciences, Physics::Geophysics, lcsh:Oceanography, Sea ice, Environmental Chemistry, CORE, 14. Life underwater, lcsh:GC1-1581, lcsh:Physical geography, Ocean circulation model, Physics::Atmospheric and Oceanic Physics, 0105 earth and related environmental sciences, Global and Planetary Change, geography, geography.geographical_feature_category, hybrid coordinates, 010505 oceanography, ocean circulation model, Model description, 13. Climate action, Climatology, General Earth and Planetary Sciences, Environmental science, Engineering research, lcsh:GB3-5030
Abstract

We document the configuration and emergent simulation features from the Geophysical Fluid Dynamics Laboratory (GFDL) OM4.0 ocean/sea ice model. OM4 serves as the ocean/sea ice component for the GFDL climate and Earth system models. It is also used for climate science research and is contributing to the Coupled Model Intercomparison Project version 6 Ocean Model Intercomparison Project. The ocean component of OM4 uses version 6 of the Modular Ocean Model and the sea ice component uses version 2 of the Sea Ice Simulator, which have identical horizontal grid layouts (Arakawa C‐grid). We follow the Coordinated Ocean‐sea ice Reference Experiments protocol to assess simulation quality across a broad suite of climate‐relevant features. We present results from two versions differing by horizontal grid spacing and physical parameterizations: OM4p5 has nominal 0.5° spacing and includes mesoscale eddy parameterizations and OM4p25 has nominal 0.25° spacing with no mesoscale eddy parameterization. Modular Ocean Model version 6 makes use of a vertical Lagrangian‐remap algorithm that enables general vertical coordinates. We show that use of a hybrid depth‐isopycnal coordinate reduces the middepth ocean warming drift commonly found in pure z* vertical coordinate ocean models. To test the need for the mesoscale eddy parameterization used in OM4p5, we examine the results from a simulation that removes the eddy parameterization. The water mass structure and model drift are physically degraded relative to OM4p5, thus supporting the key role for a mesoscale closure at this resolution.

Published
2019

22. The GFDL Earth System Model Version 4.1 (GFDL‐ESM 4.1): Overall Coupled Model Description and Simulation Characteristics

Author

Paul C.D. Milly, Elena Shevliakova, K. Rand, Yujin Zeng, Venkatramani Balaji, S. Nikonov, T. Robinson, Stephen M. Griffies, John P. Krasting, Daniel M Schwarzkopf, Lori T. Sentman, John P. Dunne, Jeffrey J. Ploshay, Jie He, Alistair Adcroft, Niki Zadeh, Huan Guo, Fabien Paulot, C. Dupuis, Larry W. Horowitz, Krista A. Dunne, Isaac M. Held, Paul Ginoux, Matthew Harrison, Robert Hallberg, Charles A. Stock, J. Durachta, Aparna Radhakrishnan, Bruce Wyman, R. Menzel, Seth Underwood, Brandon G. Reichl, Colleen McHugh, Vaishali Naik, Paul P. G. Gauthier, Chris Blanton, Sergey Malyshev, Ming Zhao, David Paynter, Michael Winton, H. Vahlenkamp, William J. Hurlin, Andrew T. Wittenberg, Jasmin G. John, and R. Dussin

Subjects
Global and Planetary Change, Meteorology, climate model, Earth system model, Model description, lcsh:Oceanography, biogeochemistry, General Earth and Planetary Sciences, Environmental Chemistry, Environmental science, Climate model, lcsh:GC1-1581, lcsh:GB3-5030, lcsh:Physical geography
Abstract

We describe the baseline coupled model configuration and simulation characteristics of GFDL's Earth System Model Version 4.1 (ESM4.1), which builds on component and coupled model developments at GFDL over 2013–2018 for coupled carbon‐chemistry‐climate simulation contributing to the sixth phase of the Coupled Model Intercomparison Project. In contrast with GFDL's CM4.0 development effort that focuses on ocean resolution for physical climate, ESM4.1 focuses on comprehensiveness of Earth system interactions. ESM4.1 features doubled horizontal resolution of both atmosphere (2° to 1°) and ocean (1° to 0.5°) relative to GFDL's previous‐generation coupled ESM2‐carbon and CM3‐chemistry models. ESM4.1 brings together key representational advances in CM4.0 dynamics and physics along with those in aerosols and their precursor emissions, land ecosystem vegetation and canopy competition, and multiday fire; ocean ecological and biogeochemical interactions, comprehensive land‐atmosphere‐ocean cycling of CO2, dust and iron, and interactive ocean‐atmosphere nitrogen cycling are described in detail across this volume of JAMES and presented here in terms of the overall coupling and resulting fidelity. ESM4.1 provides much improved fidelity in CO2 and chemistry over ESM2 and CM3, captures most of CM4.0's baseline simulations characteristics, and notably improves on CM4.0 in (1) Southern Ocean mode and intermediate water ventilation, (2) Southern Ocean aerosols, and (3) reduced spurious ocean heat uptake. ESM4.1 has reduced transient and equilibrium climate sensitivity compared to CM4.0. Fidelity concerns include (1) moderate degradation in sea surface temperature biases, (2) degradation in aerosols in some regions, and (3) strong centennial scale climate modulation by Southern Ocean convection.

Published
2020

23. The GFDL Global Atmosphere and Land Model AM4.0/LM4.0: 2. Model Description, Sensitivity Studies, and Tuning Strategies

Author

T. Robinson, Bruce Wyman, Zhaoyi Shen, Leo J. Donner, Michael Winton, John P. Dunne, Baoqiang Xiang, Paul C.D. Milly, A. R. Langenhorst, Larry W. Horowitz, Huan Guo, Daniel M Schwarzkopf, Fabien Paulot, Xi Chen, Jean-Christophe Golaz, Isaac M. Held, Venkatramani Balaji, J. R. Wilson, Krista A. Dunne, Paul Ginoux, Erik Mason, Rusty Benson, Lucas M. Harris, Venkatachalam Ramaswamy, John P. Krasting, David Paynter, Elena Shevliakova, Charles J. Seman, Pu Lin, Jan-Huey Chen, S. M. Freidenreich, Zhi Liang, Stephen T. Garner, Hyeyum Hailey Shin, J. Durachta, Andrew T. Wittenberg, Levi G. Silvers, Sergey Malyshev, Ming Zhao, Peter J. Phillipps, Aparna Radhakrishnan, Song-Miao Fan, Yi Ming, Shian-Jiann Lin, and Vaishali Naik

Subjects
Global and Planetary Change, 010504 meteorology & atmospheric sciences, Meteorology, Mode (statistics), Atmospheric Model Intercomparison Project, Forcing (mathematics), 010502 geochemistry & geophysics, 01 natural sciences, Earth system science, Geophysical fluid dynamics, General Earth and Planetary Sciences, Environmental Chemistry, Environmental science, Gravity wave, Sensitivity (control systems), 0105 earth and related environmental sciences, Orographic lift
Abstract

In Part II of this two-part paper, documentation is provided of key aspects of a version of the AM4.0/LM4.0 atmosphere/land model that will serve as a base for a new set of climate and Earth system models (CM4 and ESM4) under development at NOAA's Geophysical Fluid Dynamics Laboratory (GFDL). The quality of the simulation in AMIP (Atmospheric Model Intercomparison Project) mode has been provided in Part I. Part II provides documentation of key components and some sensitivities to choices of model formulation and values of parameters, highlighting the convection parameterization and orographic gravity wave drag. The approach taken to tune the model's clouds to observations is a particular focal point. Care is taken to describe the extent to which aerosol effective forcing and Cess sensitivity have been tuned through the model development process, both of which are relevant to the ability of the model to simulate the evolution of temperatures over the last century when coupled to an ocean model.

Published
2018
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27. Evolution and Current Status of Corporate Social Responsibility Regulation in India

Author

Aparna Radhakrishnan and Neetha Rose C D

Subjects
Aggregate expenditure, business.industry, Order (exchange), Transparency (graphic), Mandate, Corporate social responsibility, Accounting, Legislation, Enforcement, business, Companies Act
Abstract

The involvement of business firms in the growth and developmental activities in order to internalise the society's resource loss is termed as Corporate Social Responsibility (CSR). The present study examines the evolution of CSR regulations and its present status in India. India is the first country to mandate CSR spending by the corporate firms with the help of legislation, section 135 of Companies Act, 2013. Even though the act got stronger by the introduction of more strict regulations during the amendment in 2019, it lacks specific penal provision for non-compliance. Currently, the CSR compliance is 40 per cent. The aggregate CSR amount of ₹ 711.9 billion were spent in 14 different development sectors over a period of five years. The education sector received highest aggregate amount and accounted for 38 per cent of aggregate spending under CSR activities. On an average, over the last five years, number of CSR non-compliant companies has increased at the rate of 6.72 per cent and the data clearly points out the requirement of strict penalty for CSR non-compliance. The transparency in CSR disclosure and proper evaluation of CSR activity outcome is vital to understand the drawbacks which would help in refining existing regulations and developing a better enforcement strategy to obtain desired outcomes.

Published
2020
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28. Distributed Resources for the Earth System Grid Advanced Management (DREAM)

Author

Robert Ferraro, Steve Petruzza, Sasha Ames, Valerio Pascucci, L. Cinquini, Venkatramani Balaji, Giorgio Scorzelli, Aparna Radhakrishnan, L. Carriere, Jason Jerome Boutte, Thomas Maxwell, and Ghaleb Abdulla

Subjects
Computer science, Emerging technologies, business.industry, Component (UML), Scalability, Containerization, Cloud computing, Earth System Grid, Architecture, business, Software engineering, Visualization
Abstract

The DREAM project was funded more than 3 years ago to design and implement a next-generation ESGF (Earth System Grid Federation [1]) architecture which would be suitable for managing and accessing data and services resources on a distributed and scalable environment. In particular, the project intended to focus on the computing and visualization capabilities of the stack, which at the time were rather primitive. At the beginning, the team had the general notion that a better ESGF architecture could be built by modularizing each component, and redefining its interaction with other components by defining and exposing a well defined API. Although this was still the high level principle that guided the work, the DREAM project was able to accomplish its goals by leveraging new practices in IT that started just about 3 or 4 years ago: the advent of containerization technologies (specifically, Docker), the development of frameworks to manage containers at scale (Docker Swarm and Kubernetes), and their application to the commercial Cloud. Thanks to these new technologies, DREAM was able to improve the ESGF architecture (including its computing and visualization services) to a level of deployability and scalability beyond the original expectations.

Published
2019
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29. Evaluating the stationarity assumption in statistically downscaled climate projections: is past performance an indicator of future results?

Author

Anne M. K. Stoner, Katharine Hayhoe, Venkatramani Balaji, Carlos F. Gaitan, John R. Lanzante, Keith W. Dixon, Aparna Radhakrishnan, and Mary Jo Nath

Subjects
Atmospheric Science, Global and Planetary Change, 010504 meteorology & atmospheric sciences, 0208 environmental biotechnology, Climate change, Climatic variables, Regression analysis, 02 engineering and technology, 01 natural sciences, 020801 environmental engineering, Daily maximum temperature, Asynchronous communication, General Circulation Model, Climatology, Environmental science, 0105 earth and related environmental sciences, Training period, Downscaling
Abstract

Empirical statistical downscaling (ESD) methods seek to refine global climate model (GCM) outputs via processes that glean information from a combination of observations and GCM simulations. They aim to create value-added climate projections by reducing biases and adding finer spatial detail. Analysis techniques, such as cross-validation, allow assessments of how well ESD methods meet these goals during observational periods. However, the extent to which an ESD method’s skill might differ when applied to future climate projections cannot be assessed readily in the same manner. Here we present a “perfect model” experimental design that quantifies aspects of ESD method performance for both historical and late 21st century time periods. The experimental design tests a key stationarity assumption inherent to ESD methods – namely, that ESD performance when applied to future projections is similar to that during the observational training period. Case study results employing a single ESD method (an Asynchronous Regional Regression Model variant) and climate variable (daily maximum temperature) demonstrate that violations of the stationarity assumption can vary geographically, seasonally, and with the amount of projected climate change. For the ESD method tested, the greatest challenges in downscaling daily maximum temperature projections are revealed to occur along coasts, in summer, and under conditions of greater projected warming. We conclude with a discussion of the potential use and expansion of the perfect model experimental design, both to inform the development of improved ESD methods and to provide guidance on the use of ESD products in climate impacts analyses and decision-support applications.

Published
2016
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30. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

Author

Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)

Subjects
Netherlands Twin Register (NTR), Erythrocytes, Genome-wide association study, UNCERTAINTY, Regulatory Sequences, Nucleic Acid, VARIANTS, ANNOTATION, COLORECTAL-CANCER, Histones, 0302 clinical medicine, BINDING, Cluster Analysis, Myeloid Cells, Genetics (clinical), Genetics, hematological trait, 0303 health sciences, Chromosome Mapping, MRP4 ABCC4, Chromatin, Nucleosomes, Phenotype, Organ Specificity, 030220 oncology & carcinogenesis, Blood Platelets, Quantitative Trait Loci, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, DYNAMIN 3, 03 medical and health sciences, Quantitative Trait, Heritable, MEGAKARYOCYTES, Humans, Cell Lineage, ddc:610, GENOME-WIDE ASSOCIATION, Enhancer, Transcription factor, Gene, ChIA-PET, 030304 developmental biology, Research, Genetic Variation, DNA, Chromatin Assembly and Disassembly, Genetic architecture, Gene Expression Regulation, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Published
2013
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31. Pig based production system contributing towards the sustainable livelihood of the tribes of Jharkhand

Author

Jancy Gupta, Minu Singh, Aparna Radhakrishnan, and Mukesh Kumar

Subjects
Participatory rural appraisal, Economic growth, Geography, Sustainable livelihood, Pig farming, General Medicine, Traditional knowledge, Socioeconomics, Livelihood, Focus group, Natural resource, Human capital
Abstract

The present study was conducted in two randomly selected districts of Jharkhand. The study assessed the extent of Pig Based Production System Contributing towards the Sustainable Livelihood of the tribes in the Govindpur and Ormanjhi blocks of Dhanbad and Ranchi districts, respectively from 2013- 14. The data was solicited from 120 randomly selected households and the study was conducted through personal interviews of the selected respondents in the villages selected by random sampling technique, personal observations and participatory rural appraisal techniques i.e. transect walk, social mapping, key informant interview, focus group discussions. The results indicated that the livelihoods of tribal communities in the area have traditionally been dominated by the pig based production system- C+G+P. Among the sustainable livelihood components human capital was minimum compared to others and use of traditional knowledge (5.88), education of family members (5.98), ICT tools (5.95) and use of natural resources (5.71) had highest influence on sustainable livelihood of the respondents. The pig production system prevalent in the area were found to be substantially contributing for the sustainable livelihood of the respondents and were the integral part of day-to-day livelihood activities, nutritional security and traditional life style for tribal people in the area (C=Cattle, G= Goat , P=Pig).

Published
2015
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32. Vulnerability of dairy based livelihoods to climate variability and change- A study of Western Ghat Region- Ratnagiri, Maharashtra, India

Author

Aparna Radhakrishnan, Jancy Gupta, and R. DileepKumar

Subjects
General Veterinary, Animal Science and Zoology
Abstract

This study examines vulnerability of dairy based livelihoods to climate change applying index based approach underlying the principles of Intergovernmental Panel on Climate Change (IPCC), using 28 indicators to construct an overall Livelihood Vulnerability Index (LVI) to climate change, an important step in evolving appropriate adaptation strategies to climate change. Detailed house hold level data of dairy based livelihoods of Ratnagiri region of Western Ghats were collected through Participatory Rural Appraisal (PRA) and personal interviews from 180 randomly selected farmers of three talukas of Ratnagiri district complemented by thirty years of gridded weather data and other secondary data sources. The analysis revealed that the dairy farmers of Lanja taluka were most vulnerable among those of Ratnagiri district.The index score of dairy based livelihoods of Lanja taluka was negative with overall value -4.17 with 48% farmers having high level of vulnerability.

Published
2017
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33. SNP in human ARHGEF3 promoter is associated with DNase hypersensitivity, transcript level and platelet function, and Arhgef3 KO mice have increased mean platelet volume

Author

Diane S. Krause, Ping-Xia Zhang, Willem H. Ouwehand, Siying Zou, Paul F. Bray, Aparna Radhakrishnan, John Hwa, Alexandra M. Teixeira, William J. Astle, Lukas M. Simon, Lucy A. Truman, Pim van der Harst, Myrto Kostadima, Mattia Frontini, Jennifer S. Fang, Cardiovascular Centre (CVC), Astle, William [0000-0001-8866-6672], Ouwehand, Willem [0000-0002-7744-1790], Frontini, Mattia [0000-0001-8074-6299], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, Physiology, Cellular differentiation, lcsh:Medicine, 030204 cardiovascular system & hematology, Cohort Studies, Spectrum Analysis Techniques, 0302 clinical medicine, Animal Cells, Gene expression, Medicine and Health Sciences, Platelet, lcsh:Science, Promoter Regions, Genetic, Mice, Knockout, Regulation of gene expression, Multidisciplinary, Cell Differentiation, Animal Models, Hematology, Genomics, Flow Cytometry, Fetal Blood, Body Fluids, 3. Good health, INSIGHTS, Blood, DIFFERENTIATION, Experimental Organism Systems, Spectrophotometry, CARDIOVASCULAR-DISEASE, Female, Cytophotometry, Anatomy, Cellular Types, Mean Platelet Volume, Megakaryocytes, Research Article, Platelets, Blood Platelets, Gene isoform, EXPRESSION, Mouse Models, Bone Marrow Cells, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, SHAPE CHANGE, 03 medical and health sciences, Model Organisms, Genome-Wide Association Studies, Genetics, Animals, Humans, Platelet activation, Mean platelet volume, Blood Coagulation, Cell Size, Blood Cells, lcsh:R, Biology and Life Sciences, Computational Biology, PATHWAYS, Human Genetics, RHOA, Cell Biology, Platelet Activation, Genome Analysis, Molecular biology, NUCLEOTIDE EXCHANGE FACTOR, MOUSE PLATELETS, Mice, Inbred C57BL, THROMBUS FORMATION, 030104 developmental biology, Gene Expression Regulation, lcsh:Q, Hypersensitive site, Rho Guanine Nucleotide Exchange Factors, Developmental Biology
Abstract

Genome-wide association studies have identified a genetic variant at 3p14.3 (SNP rs1354034) that strongly associates with platelet number and mean platelet volume in humans. While originally proposed to be intronic, analysis of mRNA expression in primary human hematopoietic subpopulations reveals that this SNP is located directly upstream of the predominantly expressed ARHGEF3 isoform in megakaryocytes (MK). We found that ARHGEF3, which encodes a Rho guanine exchange factor, is dramatically upregulated during both human and murine MK maturation. We show that the SNP (rs1354034) is located in a DNase I hypersensitive region in human MKs and is an expression quantitative locus (eQTL) associated with ARHGEF3 expression level in human platelets, suggesting that it may be the causal SNP that accounts for the variations observed in human platelet traits and ARHGEF3 expression. In vitro human platelet activation assays revealed that rs1354034 is highly correlated with human platelet activation by ADP. In order to test whether ARHGEF3 plays a role in MK development and/or platelet function, we developed an Arhgef3 KO/LacZ reporter mouse model. Reflecting changes in gene expression, LacZ expression increases during MK maturation in these mice. Although Arhgef3 KO mice have significantly larger platelets, loss of Arhgef3 does not affect baseline MK or platelets nor does it affect platelet function or platelet recovery in response to antibody-mediated platelet depletion compared to littermate controls. In summary, our data suggest that modulation of ARHGEF3 gene expression in humans with a promoter-localized SNP plays a role in human MKs and human platelet function-a finding resulting from the biological follow-up of human genetic studies. Arhgef3 KO mice partially recapitulate the human phenotype.

Published
2017

34. Yeast Growth Plasticity Is Regulated by Environment-Specific Multi-QTL Interactions

Author

Lars M. Steinmetz, Aatish Bhatia, Anupama Yadav, Himanshu Sinha, Gyan Bhanot, Chenchen Zhu, Aparna Radhakrishnan, and Julien Gagneur

Subjects
Quantitative Trait Loci, Saccharomyces cerevisiae, Locus (genetics), Investigations, Environment, Quantitative trait locus, Biology, carbon source variation, quantitative trait locus, Yeasts, Genetics, Gene–environment interaction, gene–environment interaction, Molecular Biology, growth plasticity, Genetics (clinical), 2. Zero hunger, Phenotypic plasticity, Chromosome Mapping, food and beverages, Epistasis, Genetic, biology.organism_classification, Phenotype, Carbon, Yeast, gene–gene interaction, Epistasis, Gene-Environment Interaction
Abstract

For a unicellular, non-motile organism like Saccharomyces cerevisiae, carbon sources act both as nutrients and as signaling molecules and consequently affect various fitness parameters including growth. It is therefore advantageous for yeast strains to adapt their growth to carbon source variation. The ability of a given genotype to manifest different phenotypes in varying environments is known as phenotypic plasticity. To identify quantitative trait loci (QTL) that drive plasticity in growth, two growth parameters (growth rate and biomass) were measured in a published dataset from meiotic recombinants of two genetically divergent yeast strains grown in different carbon sources. To identify QTL contributing to plasticity across pairs of environments, gene–environment interaction mapping was performed, which identified several QTL that have a differential effect across environments, some of which act antagonistically across pairs of environments. Multi-QTL analysis identified loci interacting with previously known growth affecting QTL as well as novel two-QTL interactions that affect growth. A QTL that had no significant independent effect was found to alter growth rate and biomass for several carbon sources through two-QTL interactions. Our study demonstrates that environment-specific epistatic interactions contribute to the growth plasticity in yeast. We propose that a targeted scan for epistatic interactions, such as the one described here, can help unravel mechanisms regulating phenotypic plasticity.

Published
2014
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35. Dental management of a pediatric patient with Burkitt lymphoma: a case report

Author

M. Y. Padmanabhan, Ravinder Kumar Pandey, Archana Kumar, and Aparna Radhakrishnan

Subjects
Male, Toothbrushing, medicine.medical_specialty, medicine.medical_treatment, Xerostomia, Patient Care Planning, Humans, Medicine, Child, Intensive care medicine, Patient compliance, General Dentistry, Chemotherapy, Rehabilitation, business.industry, Chlorhexidine, Dental Prophylaxis, Cancer, Oral Hygiene, medicine.disease, Burkitt Lymphoma, Jaw Neoplasms, Lymphoma, Surgery, stomatognathic diseases, Pediatric patient, Dental Care for Chronically Ill, Anti-Infective Agents, Local, Patient Compliance, Facial Neoplasms, business, Follow-Up Studies
Abstract

Recent advancements in the field of cancer diagnosis and chemotherapy have led to higher rates of survival for children with malignant tumors. More than 75% of pediatric patients diagnosed with malignancies survive more than 5 years. These advancements have resulted in additional responsibilities for dental professionals to diagnose, evaluate, prevent, stabilize, and manage the oral and dental problems that can compromise the quality of life of these children. This case report highlights the importance of professional and self-administered oral prophylactic measures and patient compliance in the successful oral rehabilitation of a pediatric patient with Burkitt lymphoma.

Published
2012
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36. Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype

Author

Lars M. Steinmetz, Gen Lin, Julien Gagneur, Himanshu Sinha, Saumya Gupta, Aparna Radhakrishnan, and Pandu Raharja-Liu

Subjects
Transcriptional Activation, Cancer Research, Saccharomyces cerevisiae Proteins, lcsh:QH426-470, Regulator, Saccharomyces cerevisiae, Biology, Transcriptome, Genetics, Allele, Molecular Biology, Gene, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Alleles, Regulation of gene expression, Models, Genetic, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Spores, Fungal, Phenotype, Gene expression profiling, lcsh:Genetics, Meiosis, Retrograde signaling, Trans-Activators, Genome, Fungal, Research Article
Abstract

Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants’ effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression., Author Summary The causal path from a genetic variant to a complex phenotype such as disease progression is often not known. Studying gene expression variation is one approach to identify the mediating genes, however, it is difficult to distinguish causative from correlative genes. This becomes a challenge especially when studying developmental and physiological traits, since they involve dynamic processes contributing to the variation and only single static expression profiling is performed. As a proof of concept, we addressed this challenge here in yeast, by studying genome-wide gene expression in the presence of the causative polymorphism of MKT1 as the sole genetic variant, during the time phase when it contributes to sporulation efficiency variation. Our analysis during early sporulation identified mitochondrial retrograde signaling and nitrogen starvation as novel regulators, acting additively to regulate sporulation efficiency. Furthermore, we showed that PUF3, a known interactor of MKT1 had an independent role in sporulation. Our results highlight the role of differential mitochondrial signaling for efficient meiosis, providing insights into the factors regulating infertility. In addition, our study has implications for characterizing the molecular effects of causal genetic variants on dynamic biological processes during development and disease progression.

Published
2015

37. Differential regulation of antagonistic pleiotropy in synthetic and natural populations suggests its role in adaptation

Author

Anupama Yadav, Himanshu Sinha, Gyan Bhanot, and Aparna Radhakrishnan

Subjects
epistasis, QTL, Quantitative Trait Loci, Saccharomyces cerevisiae, Biology, Investigations, Balancing selection, antagonistic pleiotropy, Pleiotropy, Genetics, Genetic Pleiotropy, gene−environment interaction, Molecular Biology, Gene, Genetics (clinical), Genetic Association Studies, Recombination, Genetic, Natural selection, Chromosome Mapping, Epistasis, Genetic, Ras/PKA pathway, Phenotype, Adaptation, Physiological, Cyclic AMP-Dependent Protein Kinases, Genetics, Population, ras Proteins, Epistasis, Gene-Environment Interaction, Adaptation, Gene Deletion, Signal Transduction
Abstract

Antagonistic pleiotropy (AP), the ability of a gene to show opposing effects in different phenotypes, has been identified in various life history traits and complex disorders, indicating its fundamental role in balancing fitness over the course of evolution. It is intuitive that natural selection might maintain AP to allow organisms phenotypic flexibility in different environments. However, despite several attempts, little evidence exists for its role in adaptation. We performed a meta-analysis in yeast to identify the genetic basis of AP in bi-parental segregants, natural isolates, and a laboratory strain genome-wide deletion collection, by comparing growth in favorable and stress conditions. We found that whereas AP was abundant in the synthetic populations, it was absent in the natural isolates. This finding indicated resolution of trade-offs, i.e., mitigation of trade-offs over evolutionary history, probably through accumulation of compensatory mutations. In the deletion collection, organizational genes showed AP, suggesting ancient resolutions of trade-offs in the basic cellular pathways. We find abundant AP in the segregants, greater than estimated in the deletion collection or observed in previous studies, with IRA2, a negative regulator of the Ras/PKA signaling pathway, showing trade-offs across diverse environments. Additionally, IRA2 and several other Ras/PKA pathway genes showed balancing selection in isolates of S. cerevisiae and S. paradoxus, indicating that multiple alleles maintain AP in this pathway in natural populations. We propose that during AP resolution, retaining the ability to vary signaling pathways such as Ras/PKA, may provide organisms with phenotypic flexibility. However, with increasing organismal complexity AP resolution may become difficult. A partial resolution of AP could manifest as complex human diseases, and the inability to resolve AP may play a role in speciation. Our findings suggest that testing a universal phenomenon like AP across multiple experimental systems may elucidate mechanisms underlying its regulation and evolution.

Published
2015

38. Vulnerability of Dairy-Based Livelihoods to Climate Variability and Change:A Study of Western Ghats Region in Wayanad, Kerala

Author

Aparna Radhakrishnan and Jancy Gupta

Subjects
Participatory rural appraisal, Adaptive capacity, Multidisciplinary, Geography, Vulnerability index, Environmental protection, Vulnerability, Climate change, Sustenance, Socioeconomics, Livelihood, Dairy farming
Abstract

The study assesses the livelihood vulnerability of dairy farmers to climate variability and change (CVC) in Wayanad district of the Western Ghats region in Kerala. For this purpose, a Livelihood Vulnerability Index (LVI) was developed underlying the definition of Intergovernmental Panel on Climate Change consisting of 28 indicators and 7 LVI components. A fussel framework was used for conceptualizing the vulnerable situation. Participatory rural appraisal and personal interviews were used to collect household data of 180 dairy farmers of three taluks complemented by thirty years of gridded weather data. The normalized data were then combined into three indices, i.e. sensitivity, exposure and adaptive capacity, which were then averaged with weights given using principal component analysis, to obtain the overall index. LVI indicated that the dairy farmers of all the taluks of Wayanad are vulnerable to CVC with Pulpally taluka being the most vulnerable with 48.33% farmers under the high level vulnerability category with wide variation in LVI components across the taluks. For the sustenance of dairy farming of small and marginal farmers of the region and for mitigating risks, policies are required for incentivizing the livelihood infrastructure and promotion of grass root level innovations.

Published
2017
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39. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Author

Zhaoming Wang, André Scherag, James F. Wilson, Nancy L. Heard-Costa, Ingrid B. Borecki, Sang Hong Lee, Veronique Vitart, Zoltán Kutalik, Jeffrey R. O'Connell, Mieke D. Trip, Lu Qi, Peter Vollenweider, Jennifer L. Bragg-Gresham, Davide Gentilini, Kees Hovingh, Lynda M. Rose, Carolin Pütter, Martin Farrall, Albert V. Smith, Nicholas G. Martin, Tõnu Esko, David J. Hunter, Georg Homuth, Liming Liang, Yudi Pawitan, Winfried März, George Dedoussis, Irene Mateo Leach, Nicholas J. Wareham, Lars Lind, Thomas Illig, Andrew P. Morris, Daniele Cusi, Jouke-Jan Hottenga, Tove Fall, Themistocles L. Assimes, Massimo Mangino, Dmitry Shungin, Kari Stefansson, Anne U. Jackson, Inês Barroso, Sarah E. Medland, Lude Franke, Karen L. Mohlke, Folkert W. Asselbergs, Sarah E. Hunt, Gudmar Thorleifsson, Pablo V. Gejman, Serena Sanna, Mark I. McCarthy, David M. Evans, Joel N. Hirschhorn, Alan F. Wright, Sarah H. Wild, Patricia B. Munroe, Marcel Bruinenberg, Gonneke Willemsen, Ulf de Faire, Markku Laakso, Marja-Liisa Lokki, Andrew C. Heath, Jing Hua Zhao, Lavinia Paternoster, Jana V. van Vliet-Ostaptchouk, Sailaja Vedantam, Danyu Lin, Eric E. Schadt, Stefano Signorini, Harald Grallert, Tsegaselassie Workalemahu, Jonathan Tyrer, Albert Hofman, George Nicholson, Patrik K. E. Magnusson, Arthur W. Musk, Jian Yang, Vilmundur Gudnason, Robert C. Kaplan, Panos Deloukas, Nilesh J. Samani, Inke R. König, Frank B. Hu, Paul M. Ridker, Tamara B. Harris, Bruce H. R. Wolffenbuttel, Ellen A. Nohr, Sarah Edkins, Lambertus A. Kiemeney, Anke Hinney, Eric Boerwinkle, Klaus Stark, Ben A. Oostra, Barbara Thorand, Unnur Thorsteinsdottir, Meena Kumari, Evelin Mihailov, Caroline S. Fox, Michael Boehnke, Aroon D. Hingorani, Jonathan Stephens, Kathleen Stirrups, Inga Prokopenko, Anke Tönjes, Lili Milani, John Beilby, Carlos Iribarren, Kari E. North, Cécile Lecoeur, So-Youn Shin, Marjo-Riitta Järvelin, Matti Uusitupa, Åsa Johansson, Nancy L. Pedersen, Krista Fischer, Fernando Rivadeneira, Wolfgang Koenig, Fredrik Karpe, Antti Jula, Lindsay L. Waite, Gérard Waeber, Mustafa Atalay, Heribert Schunkert, Narisu Narisu, Sita H. Vermeulen, Bernhard R. Winkelmann, Guo Li, Anders Hamsten, Elizabeth K. Speliotes, Ivonne Jarick, Sirkka Keinänen-Kiukaanniemi, L. Adrienne Cupples, Ruth J. F. Loos, Martina Müller-Nurasyid, David-Alexandre Trégouët, Claudia Langenberg, Willem H. Ouwehand, Julius S. Ngwa, Jennifer E. Huffman, H-Erich Wichmann, Amy J. Swift, Marco M Ferrario, Leif Groop, Henrik Grönberg, Peter M. Visscher, Claes Ohlsson, Markku S. Nieminen, Aparna Radhakrishnan, Harold Snieder, Devin Absher, Albertine J. Oldehinkel, Erik Ingelsson, Anna Maria Di Blasio, M. Carola Zillikens, Veikko Salomaa, Colin N. A. Palmer, Lori L. Bonnycastle, Teresa Ferreira, Ronald P. Stolk, Annette Peters, Philippe Froguel, Michael Stumvoll, David Schlessinger, Maria Dimitriou, Timo Saaristo, Cristen J. Willer, Jarmo Virtamo, Jorma Viikari, Alena Stančáková, Mika Kivimäki, Paolo Brambilla, Jaakko Tuomilehto, Dorret I. Boomsma, Harry Campbell, Jianjun Liu, Daniel I. Chasman, Gonçalo R. Abecasis, Ilja M. Nolte, Karl-Heinz Jöckel, Reedik Mägi, Pamela A. F. Madden, Jaana Laitinen, Sonja I. Berndt, Frank Kee, Marcus E. Kleber, Jacqueline C.M. Witteman, Jouko Saramies, Francis S. Collins, Johan G. Eriksson, Melanie M. van der Klauw, Yi-Juan Hu, John F. Peden, Markus Perola, Henri Wallaschofski, Jean Ferrières, Elena Tremoli, Marjolein J. Peters, Olli T. Raitakari, Claudia Lamina, Sekar Kathiresan, Mary F. Feitosa, Diana Kuh, Tim D. Spector, Paul W. Franks, Gerjan Navis, Martin den Heijer, Christian Gieger, Kevin B. Jacobs, Andrea Ganna, Timothy M. Frayling, Iris M. Heid, Bernhard O. Boehm, Eleanor Wheeler, Sonali Pechlivanis, Miriam F. Moffatt, Brenda W.J.H. Penninx, Anna-Liisa Hartikainen, Augusto Rendon, Stefan Schreiber, Stephen J. Chanock, Andrew R. Wood, Jianxin Shi, Najaf Amin, Lenore J. Launer, Michael A. Province, Jeanette Erdmann, Mattias Lorentzon, Hugh Watkins, Johanna Kuusisto, John-Olov Jansson, David P. Strachan, Anne E. Justice, Toby Johnson, Cornelia M. van Duijn, Niina Eklund, Samuli Ripatti, Aarno Palotie, Aldi T. Kraja, Michael Preuss, Rona J. Strawbridge, Ozren Polasek, Elisabeth Widen, Barbara McKnight, Mariano Dei, Vincent Mooser, Josine L. Min, Caroline Hayward, Mika Kähönen, Peter P. Pramstaller, Femmie de Vegt, Rainer Rauramaa, Douglas F. Levinson, Diana Marek, Antonio Liuzzi, Stefan Gustafsson, Andrew A. Hicks, Gemma Cadby, Damien C. Croteau-Chonka, Mark J. Caulfield, Boris Skrobek, Lyle J. Palmer, Alexander Teumer, Ken K. Ong, Ulf Gyllensten, Anneli Pouta, Anuj Goel, Eva Albrecht, Kristian Hveem, Inger Njølstad, David Meyre, Ida Surakka, Francesca Frau, Paolo Manunta, Sabine Schipf, Carolina Medina-Gomez, Kay-Tee Khaw, Alan R. Sanders, Thorkild I. A. Sørensen, André G. Uitterlinden, Alistair S. Hall, Felix R. Day, Karol Estrada, Jennifer G. Sambrook, Eirini V. Theodoraki, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Talin Haritunian, Benjamin M. Neale, Juha Sinisalo, Kati Kristiansson, Thomas W. Winkler, Pim van der Harst, Peter S. Chines, Joyce B. J. van Meurs, Wendy L. McArdle, Andrew Wong, Grant W. Montgomery, Terho Lehtimäki, Igor Rudan, Keri L. Monda, John M. C. Connell, Jian'an Luan, Per Hall, Joshua C. Randall, Anthony J. Balmforth, Chris Power, Philippe Amouyel, Andres Metspalu, Johannes Hebebrand, Andrew D. Morris, Jaana Lindström, Liesbeth Vandenput, William O.C.M. Cookson, Hanneke Basart, Stavroula Kanoni, Elina Hyppönen, Christian Hengstenberg, Thomas W. Mühleisen, Kari Kuulasmaa, Timo A. Lakka, Nicole Soranzo, Bruce M. Psaty, Antony P. Attwood, Epidemiology, Clinical Genetics, Surgery, Erasmus School of Social and Behavioural Sciences, Public Health, Internal Medicine, Immunology, Child and Adolescent Psychiatry / Psychology, Internal medicine, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Other departments, Vascular Medicine, Biological Psychology, Cognitive Psychology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Esko, T, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Luan, J, Randall, J, Vedantam, S, Willer, C, Winkler, T, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Huffman, J, Jarick, I, Johansson, Å, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mangino, M, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Teumer, A, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Zhao, J, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, Brambilla, P, Bruinenberg, M, Campbell, H, Chasman, D, Chines, P, Collins, F, Connell, J, Cookson, W, De, F, U, D, Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Evans, D, Farrall, M, Ferrario, M, Ferrières, J, Franke, L, Frau, F, Gejman, P, Grallert, H, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, Homuth, G, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimäki, M, Koenig, W, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Mateo Leach, I, Mcknight, B, Medland, S, Mihailov, E, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Navis, G, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palmer, C, Palotie, A, Peden, J, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stančáková, A, Stark, K, Stephens, J, Stirrups, K, Stolk, R, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widén, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Zillikens, M, Amouyel, P, Boehm, B, Boerwinkle, E, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Metspalu, A, Morris, A, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Snieder, H, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, van der Harst, P, Vollenweider, P, Wallaschofski, H, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Heid, I, Hunter, D, Kaplan, R, Karpe, F, Moffatt, M, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, Van, D, Cm, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Scherag, A, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Medical Research Council (MRC), Berndt, Sonja I, Gustafsson, Stefan, Mägi, Reedik, Ganna, Andrea, Lee, Sang Hong, Hyppönen, Elina Tuulikki, Ingelsson, Erik, Berndt, Si, Feitosa, Mf, Justice, Ae, Monda, Kl, CROTEAU CHONKA, Dc, Day, Fr, Jackson, Au, Randall, Jc, Willer, Cj, Winkler, Tw, Wood, Ar, Hu, Yj, Lee, Sh, Lin, Dy, Min, Jl, Neale, Bm, BRAGG GRESHAM, Jl, DEN HEIJER, M, Hottenga, Jj, Huffman, Je, Johansson, A, Kleber, Me, König, Ir, Mcardle, Wl, MEDINA GOMEZ, C, MÜLLER NURASYID, M, Nolte, Im, Peters, Mj, Rose, Lm, Smith, Av, Strawbridge, Rj, Trip, Md, VAN VLIET OSTAPTCHOUK, Jv, Waite, Ll, Zhao, Jh, Asselbergs, Fw, Attwood, Ap, Balmforth, Aj, Bonnycastle, Ll, Chasman, Di, Connell, Jm, Cookson, Wo, DE FAIRE, U, DE VEGT, F, Evans, Dm, Ferrario, Mm, Gejman, Pv, Hartikainen, Al, HEARD COSTA, Nl, Heath, Ac, Hu, Fb, Hunt, Se, Jacobs, Kb, Jansson, Jo, Khaw, Kt, Kraja, At, Laitinen, Jh, Lakka, Ta, Launer, Lj, Lokki, Ml, Madden, Pa, Magnusson, Pk, Manunta, Paolo, MATEO LEACH, I, Medland, Se, Montgomery, Gw, Mühleisen, Tw, Munroe, Pb, Musk, Aw, Nohr, Ea, Ong, Kk, Oostra, Ba, Palmer, Cn, Peden, Jf, Pramstaller, Pp, Saaristo, Te, Sambrook, Jg, Sanders, Ar, Shin, Sy, Stephens, Jc, Stolk, Rp, Swift, Aj, Theodoraki, Ev, Tregouet, Da, VAN DER KLAUW, Mm, VAN MEURS, Jb, Vermeulen, Sh, Wild, Sh, Winkelmann, Br, Witteman, Jc, Wolffenbuttel, Bh, Wright, Af, Zillikens, Mc, Boehm, Bo, Boomsma, Di, Caulfield, Mj, Chanock, Sj, Cupples, La, Dedoussis, Gv, Eriksson, Jg, Franks, Pw, Harris, Tb, Hicks, Aa, Hovingh, Kg, Jarvelin, Mr, Jöckel, Kh, KEINANEN KIUKAANNIEMI, Sm, Kiemeney, La, Levinson, Df, Martin, Ng, Morris, Ad, Oldehinkel, Aj, Ouwehand, Wh, Palmer, Lj, Province, Ma, Psaty, Bm, Ridker, Pm, Samani, Nj, Sørensen, Ti, Spector, Td, Uitterlinden, Ag, VAN DER HARST, P, Wareham, Nj, Wichmann, He, Wilson, Jf, Abecasis, Gr, Assimes, Tl, Borecki, Ib, Groop, Lc, Heid, Im, Kaplan, Rc, Moffatt, Mf, Mohlke, Kl, O'Connell, Jr, Schadt, Ee, Strachan, Dp, VAN DUIJN, Cm, Visscher, Pm, DI BLASIO, Am, Hirschhorn, Jn, Lindgren, Cm, Morris, Ap, Mccarthy, Mi, Speliotes, Ek, North, Ke, Loos, Rj, and Ingelsson, E.

Subjects
Netherlands Twin Register (NTR), Linkage disequilibrium, SORTILIN, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Medizin, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], polymorphism, Body Mass Index, 0302 clinical medicine, Missing heritability problem, MISSING HERITABILITY, EXTREME OBESITY, CONFER RISK, POPULATION, Genetics & Heredity, 2. Zero hunger, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, Anthropometry, COMMON VARIANTS, Single Nucleotide, ASSOCIATION, Biological Sciences, Anthropometry, Body Height, genetics, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, genetics, Phenotype, Polymorphism, genetics, Quantitative Trait Loci, Waist-Hip Ratio, Phenotype, Life Sciences & Biomedicine, EXPRESSION, Genotype, Missing heritabillity, Population, European Continental Ancestry Group, Quantitative Trait Loci, EARLY-ONSET, Genomics, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Obesity, body height/genetics, Polymorphism, Allele, Genetik, education, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Science & Technology, Waist-Hip Ratio, BMI, height, WHR, obesity, GWS, ta3121, Genetic architecture, Body Height, BODY-MASS INDEX, Case-Control Studies, gene, stature, height, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. © 2013 Nature America, Inc. All rights reserved.

Published
2013
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40. Seventy-five genetic loci influencing the human red blood cell

Author

Teresa Nutile, Anna-Liisa Hartikainen, Stavroula Kanoni, Johannes H. Smit, Harm-Jan Westra, Beben Benyamin, Gonneke Willemsen, Clara S. Tang, Maria Dimitriou, Peter Vollenweider, Olle Melander, Inga Prokopenko, W.H. Wilson Tang, John P. Kemp, Tim D. Spector, Evelin Mihailov, Paul F. O'Reilly, Eleonora Porcu, Marcus E. Kleber, Sheila Ulivi, George Dedoussis, Manuela Uda, Matthias Nauck, Brenda W.J.H. Penninx, Daniela Ruggiero, Xinzhong Li, Dirk S. Paul, Niek Verweij, Bernd Genser, Harold Snieder, Willem H. Ouwehand, Ido P. Kema, Miriam F. Moffatt, Carmel Moore, Hilma Holm, Nicola Pirastu, Adamo Pio D'Adamo, Michael Stumvoll, Rossella Sorice, Kay-Tee Khaw, Heather Lloyd-Jones, Federico Murgia, Stephen F. Garner, Jing Hua Zhao, Laura Portas, Abdel Abdellaoui, Ursula Puc, Andres Metspalu, Marleen H. M. de Moor, Isleifur Olafsson, Ruth J. F. Loos, Andres Salumets, François Bastardot, James Scott, Jian Yang, Braxton D. Mitchell, Debora Parracciani, Maria Novatchkova, Panos Deloukas, William O.C.M. Cookson, Lorna M. Lopez, Andrew A. Hicks, Aude Saint-Pierre, Daniel F. Gudbjartsson, Vinicius Tragante, Mario Pirastu, Jacques S. Beckmann, L. Joost van Pelt, Winfried Maerz, Hooman Allayee, Jouke-Jan Hottenga, Kari Stefansson, Debashish Das, Weihua Zhang, Anke Tönjes, Michela Traglia, Stuart Meacham, Antonio Piga, Cornelis A. Albers, Nicholas G. Martin, John C. Chambers, Christa Meisinger, Leo-Pekka Lyytikäinen, Nicole Soranzo, Mika Kähönen, Katrin Voss, Micha Hersch, Claudia Langenberg, Sian Tsung Tan, Sandosh Padmanabhan, Christian X. Weichenberger, J. Gustav Smith, Antony P. Attwood, Claire E. Hastie, Gunnar Engström, Janina S. Ried, Carsten Oliver Schmidt, Pall T. Onundarson, Kathy Miller, Francisco S. Domingues, Stefania Bandinelli, Ulrich Elling, Augusto Rendon, Paul Elliott, Quince Gibson, Tõnu Esko, Robert Sladek, Marina Ciullo, Gerald Wirnsberger, Franco Anni, Antonietta Robino, Serena Sanna, Hein Schepers, Jonathan Stephens, Joban Sehmi, Beverley Balkau, Jennifer G. Sambrook, Lucia Perseu, Ilja M. Nolte, Herman H W Silljé, John M. Starr, Cinzia Sala, Peter P. Pramstaller, David M. Evans, Renzo Galanello, Uwe Völker, Philippe Froguel, Dorret I. Boomsma, Vasiliki Lagou, Gerjan Navis, Christian Gieger, Susan M. Ring, Alexander Teumer, Angela Döring, Ale Algra, Toshiko Tanaka, Bo Hedblad, Anneli Pouta, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Liming Liang, John Danesh, Paolo Gasparini, Sarah E. Medland, Ian J. Deary, Martin Gögele, Pim van der Harst, Giorgia Girotto, Josef M. Penninger, Jaspal S. Kooner, Patrick Sulem, Thomas Illig, Yasin Memari, Sarah E. Harris, Wiek H. van Gilst, Francesco Cucca, Dirk J. van Veldhuisen, So-Youn Shin, Giorgio Pistis, Olli T. Raitakari, Lude Franke, Folkert W. Asselbergs, Abtehale Al-Hussani, Stanley L. Hazen, Manuel A. R. Ferreira, Aimo Ruokonen, Christian Dina, Aparna Radhakrishnan, Irene Mateo Leach, Nicholas J. Wareham, George Davey Smith, Eric E. Schadt, Alan R. Shuldiner, John Whitfield, Gudmundur I. Eyjolfsson, Eco J. C. de Geus, Grant W. Montgomery, Afshin Parsa, Terho Lehtimäki, Paolo Fortina, Luigi Ferrucci, Andreas Greinacher, Marjo-Riitta Järvelin, Krista Fischer, Fabrice Danjou, Rudolf A. de Boer, Paul I.W. de Bakker, Peter M. Visscher, Anna F. Dominiczak, Ramiro Ramirez-Solis, Jennifer Jolley, Bruce H. R. Wolffenbuttel, Jaana Hartiala, Daniela Toniolo, Bernhard O. Boehm, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, St, Voss, K, Weichenberger, Cx, Albers, Ca, Al Hussani, A, Asselbergs, Fw, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, Dm, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, Jj, Kanoni, S, Kleber, Me, Lagou, V, Langenberg, C, Lopez, Lm, Lyytikäinen, Lp, Melander, O, Murgia, F, Nolte, Im, O'Reilly, Pf, Padmanabhan, S, Parsa, A, Pirastu, Nicola, Porcu, E, Portas, L, Prokopenko, I, Ried, J, Shin, Sy, Tang, C, Teumer, A, Traglia, Michela, Ulivi, S, Westra, Hj, Yang, J, Zhao, Jh, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, Bo, Cookson, Wo, Das, D, de Bakker, Pi, de Boer, Ra, de Geus, Ej, de Moor, Mh, Dimitriou, M, Domingues, F, Döring, A, Engström, G, Eyjolfsson, Gi, Ferrucci, L, Fischer, K, Galanello, R, Garner, Sf, Genser, B, Gibson, Qd, Girotto, Giorgia, Gudbjartsson, Df, Harris, Se, Hartikainen, Al, Hastie, Ce, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, Ip, Kemp, Jp, Liang, L, Lloyd Jones, H, Loos, Rj, Meacham, S, Medland, Se, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, Mf, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, Pt, Parracciani, D, Penninx, Bw, Perseu, L, Piga, A, Pistis, G, Pouta, A, Puc, U, Raitakari, O, Ring, Sm, Robino, Antonietta, Ruggiero, D, Ruokonen, A, Saint Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, Co, Silljé, Hh, Sladek, R, Smit, Jh, Starr, Jm, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, Wh, van Pelt, Lj, van Veldhuisen, Dj, Völker, U, Whitfield, Jb, Willemsen, G, Winkelmann, Br, Wirnsberger, G, Algra, A, Cucca, F, D'Adamo, ADAMO PIO, Danesh, J, Deary, Ij, Dominiczak, Af, Elliott, P, Fortina, P, Froguel, P, Gasparini, Paolo, Greinacher, A, Hazen, Sl, Jarvelin, Mr, Khaw, Kt, Lehtimäki, T, Maerz, W, Martin, Ng, Metspalu, A, Mitchell, Bd, Montgomery, Gw, Moore, C, Navis, G, Pirastu, M, Pramstaller, Pp, Ramirez Solis, R, Schadt, E, Scott, J, Shuldiner, Ar, Smith, Gd, Smith, Jg, Snieder, H, Sorice, R, Spector, Td, Stefansson, K, Stumvoll, M, Tang, Wh, Toniolo, D, Tönjes, A, Visscher, Pm, Vollenweider, P, Wareham, Nj, Wolffenbuttel, Bh, Boomsma, Di, Beckmann, J, Dedoussis, Gv, Deloukas, P, Ferreira, Ma, Sanna, S, Uda, M, Hicks, Aa, Penninger, Jm, Gieger, C, Kooner, J, Ouwehand, Wh, Soranzo, N, Chambers, J. C., Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Van Der Harst, Pim, Zhang, Weihua, Mateo Leach, Irene, Rendon, Augusto, Benyamin, Beben, Chambers, John C, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
Male, Netherlands Twin Register (NTR), Candidate gene, Erythrocytes, PROTEIN, Genome-wide association study, DISEASE, Hemoglobins, Mice, 0302 clinical medicine, Genetics, Genomics, blood, 0303 health sciences, Multidisciplinary, biology, Cell Cycle, COMMON VARIANTS, Genomics, Phenotype, anemia, 3. Good health, Haematopoiesis, DROSOPHILA, Drosophila melanogaster, medicine.anatomical_structure, HEMOGLOBIN LEVELS, Organ Specificity, 030220 oncology & carcinogenesis, Cytokines, Female, RNA Interference, TRAITS, Signal Transduction, EXPRESSION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic, blood, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, RECEPTOR, CONSORTIUM, ta3121, hemoglobin, biology.organism_classification, Hematopoiesis, meta-analysis, Red blood cell, Gene Expression Regulation, Genetic Loci, Expression quantitative trait loci, genome-wide association studies, Genome-Wide Association Study
Abstract

Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Published
2012
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41. Correction: Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Author

Toshiko Tanaka, Clara Camaschella, Niek Verweij, Denise Anderson, Peter Vollenweider, Nicholas G. Martin, Stefania Bandinelli, Andres Metspalu, Peter P. Pramstaller, Dorine W. Swinkels, Maristella Steri, Ayse Demirkan, Serena Sanna, Jennifer Jolley, Irene Pichler, Pamela A. F. Madden, Gérard Waeber, Lambertus A. Kiemeney, Clara Podmore, Daniela Toniolo, Jennie Hui, Tõnu Esko, Thomas Meitinger, Jennifer G. Sambrook, Jiaåan Luan, Andrew A. Hicks, Joachim Thiery, Claudia Langenberg, Andrew Heath, Robert A. Scott, Aaron Isaacs, Peter van der Meer, Cornelia M. van Duijn, Juliane Winkelmann, Fudi Wang, Peter M. Visscher, Fred C.G.J. Sweep, Zoltán Kutalik, Annette Peters, Michela Traglia, Cinzia Sala, Manuela Uda, Augusto Rendon, Melanie Waldenberger, Christian Gieger, Lili Milani, John Beilby, Margaret J. Wright, Konrad Oexle, Christine Schwienbacher, Linda Broer, Grant W. Montgomery, Najaf Amin, Dale R. Nyholt, Martin Gögele, Pim van der Harst, Dena G. Hernandez, Janina S. Ried, Aparna Radhakrishnan, Nicholas J. Wareham, Sita H. Vermeulen, John Whitfield, Harm-Jan Westra, Beben Benyamin, Joseph E. Powell, Evelin Mihailov, Lude Franke, Jonas Hälldin, Willem H. Ouwehand, Benyamin, B, Esko, T, Ried, J, Radhakrishnan, A, Vermeulen, Sh, Traglia, M, Gögele, M, Anderson, D, Broer, L, Podmore, C, Luan, J, Kutalik, Z, Sanna, S, VAN DER MEER, P, Tanaka, T, Wang, F, Westra, Hj, Franke, L, Mihailov, E, Milani, L, Hälldin, J, Winkelmann, J, Meitinger, T, Thiery, J, Peters, A, Waldenberger, M, Rendon, A, Jolley, J, Sambrook, J, Kiemeney, La, Sweep, Fc, Sala, Cf, Schwienbacher, C, Pichler, I, Hui, J, Demirkan, A, Isaacs, A, Amin, N, Steri, M, Waeber, G, Verweij, N, Powell, Je, Nyholt, Dr, Heath, Ac, Madden, Pa, Visscher, Pm, Wright, Mj, Montgomery, Gw, Martin, Ng, Hernandez, D, Bandinelli, S, VAN DER HARST, P, Uda, M, Vollenweider, P, Scott, Ra, Langenberg, C, Wareham, Nj, VAN DUIJN, C, Beilby, J, Pramstaller, Pp, Hicks, Aa, Ouwehand, Wh, Oexle, K, Gieger, C, Metspalu, A, Camaschella, Clara, Toniolo, D, Swinkels, Dw, and Whitfield, Jb

Subjects
Genetics, Multidisciplinary, General Physics and Astronomy, General Chemistry, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Iron homeostasis, 030220 oncology & carcinogenesis, medicine, 030217 neurology & neurosurgery, Hemochromatosis
Abstract

Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Published
2015
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43. Pulse Granuloma as a Complication Following Dental Trauma in Children.

Author

Padmanabhan, Makkada Yuvaraj, Aparna, Radhakrishnan, Karthikeyani, Shanmugasundaram, Dinakar, Jayakumar, and Manickaraj, Menaka

Subjects
*ANALGESICS, *ACCIDENTAL falls, *FOREIGN bodies, *GINGIVAL hyperplasia, *GRANULOMA, *HEMORRHAGE, *INCISORS, *TUMORS, *DIAGNOSIS
Abstract

Contamination and subsequent retention of foreign bodies within wound surfaces may negatively influence healing following maxillofacial injuries. Larger foreign bodies that produce embedded or impalement injuries of soft tissues are easily detected. However, smaller contaminants, such as sand, gravel, food particles, wood splinters, and glass fibers, may not be easily identified in the initial examination, and their remnants may remain within the injury site even after debridement. Tissue reactions depend on the host response, type of foreign body, and nature of the wound surface. The purposes of this report are to: (1) detail the diagnosis and management of a peripheral pulse granuloma following retention of food particles within gingival sulci during a dental injury; and (2) provide a brief review of the diagnosis of foreign body-induced granulomas following maxillofacial injuries in children. [ABSTRACT FROM AUTHOR]

Published
2013

44. New gene functions in megakaryopoiesis and platelet formation

Author

Christian Gieger1, Aparna Radhakrishnan2, 3, Ana Cvejic2, Weihong Tang4, Eleonora Porcu5, Giorgio Pistis6, Jovana Serbanovic-Canic2, Ulrich Elling7, Alison H. Goodall8, 9, Yann Labrune10, Lorna M. Lopez11, Reedik Ma¨gi13, Stuart Meacham2, Yukinori Okada14, Nicola Pirastu16, 102, Rossella Sorice17, Alexander Teumer18, Katrin Voss2, Weihua Zhang19, Ramiro Ramirez-Solis3, Joshua C. Bis20, David Ellinghaus21, Martin Go¨ gele22, Jouke-Jan Hottenga23, Claudia Langenberg24, Peter Kovacs25, Paul F. O'Reilly26, So-Youn Shin3, To~nu Esko28, Jaana Hartiala31, Stavroula Kanoni3, Federico Murgia34, Afshin Parsa35, Jonathan Stephens2, Pim van der Harst36, C. Ellen van der Schoot37, Hooman Allayee31, Antony Attwood2, Beverley Balkau38, François Bastardot40, Saonli Basu41, Sebastian E. Baumeister42, Ginevra Biino34, Lorenzo Bomba45, Ame´lie Bonnefond10, François Cambien46, John C. Chambers19, Francesco Cucca5, Pio D'Adamo16, Gail Davies12, Rudolf A. de Boer36, Eco J. C. de Geus23, Angela Do¨ ring47, Paul Elliott19, Jeanette Erdmann50, 101, David M. Evans51, Mario Falchi52, Wei Feng41, Aaron R. Folsom4, Ian H. Frazer53, Quince D. Gibson35, Nicole L. Glazer54, Chris Hammond27, Anna-Liisa Hartikainen55, Susan R. Heckbert56, Christian Hengstenberg58, Micha Hersch59, Thomas Illig60, Ruth J. F. Loos24, Jennifer Jolley2, Kay Tee Khaw61, Brigitte Ku¨hnel1, Marie-Christine Kyrtsonis63, Vasiliki Lagou64, Heather Lloyd-Jones2, Thomas Lumley65, Massimo Mangino27, Andrea Maschio5, Irene Mateo Leach36, Barbara McKnight65, Yasin Memari3, Braxton D. Mitchell35, Grant W. Montgomery66, Yusuke Nakamura67, Matthias Nauck68, Gerjan Navis69, Ute No¨ thlings70, Ilja M. Nolte72, David J. Porteous11, Anneli Pouta55, Peter P. Pramstaller22, Janne Pullat28, Susan M. Ring51, Jerome I. Rotter75, Daniela Ruggiero17, Aimo Ruokonen76, Cinzia Sala6, Nilesh J. Samani8, Jennifer Sambrook2, David Schlessinger78, Stefan Schreiber21, Heribert Schunkert50, James Scott79, Nicholas L. Smith56, Harold Snieder72, John M. Starr11, Michael Stumvoll82, Atsushi Takahashi14, W. H. Wilson Tang83, Kent Taylor75, Albert Tenesa85, Swee Lay Thein87, Anke To¨njes82, Manuela Uda5, Sheila Ulivi16, Dirk J. van Veldhuisen36, Peter M. Visscher11, Uwe Vo¨lker18, H.-Erich Wichmann47, Kerri L. Wiggins20, Gonneke Willemsen23, Tsun-Po Yang3, Jing Hua Zhao24, Paavo Zitting89, John R. Bradley77, George V. Dedoussis33, Paolo Gasparini16, Stanley L. Hazen83, Andres Metspalu28, Mario Pirastu34, Alan R. Shuldiner35, L. Joost van Pelt91, Jaap-Jan Zwaginga92, Dorret I.Boomsma23, Ian J. Deary11, Andre Franke21, Philippe Froguel10, Santhi K. Ganesh93, Marjo-Riitta Jarvelin26, Nicholas G. Martin66, Christa Meisinger48, Bruce M. Psaty57, Timothy D. Spector27, Nicholas J. Wareham24, Jan-Willem N. Akkerman97, Marina Ciullo17, Panos Deloukas3, Andreas Greinacher98, Steve Jupe99, Naoyuki Kamatani14, Jyoti Khadake99, Jaspal S. Kooner79, Josef Penninger7, Inga Prokopenko64, Derek Stemple3, Daniela Toniolo6, Lorenz Wernisch100, Serena Sanna5, Andrew A. Hicks22, Augusto Rendon2, 100, Manuel A. Ferreira 66, Willem H. Ouwehand 2, Nicole Soranzo3, Christian, Gieger, Aparna, Radhakrishnan, Ana, Cvejic, Weihong, Tang, Eleonora, Porcu, Giorgio, Pisti, Jovana Serbanovic, Canic, Ulrich, Elling, Alison H., Goodall, Yann, Labrune, Lorna M., Lopez, Reedik, Mägi, Stuart, Meacham, Yukinori, Okada, Pirastu, Nicola, Rossella, Sorice, Alexander, Teumer, Katrin, Vo, Weihua, Zhang, Ramiro Ramirez, Soli, Joshua C., Bi, David, Ellinghau, Martin, Gögele, Jouke Jan, Hottenga, Claudia, Langenberg, Peter, Kovac, Paul F., O’Reilly, So Youn, Shin, Tõnu, Esko, Jaana, Hartiala, Stavroula, Kanoni, Federico, Murgia, Afshin, Parsa, Jonathan, Stephen, Pim van der, Harst, C., Ellen van der Schoot, Hooman, Allayee, Antony, Attwood, Beverley, Balkau, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Ginevra, Biino, Lorenzo, Bomba, Amélie, Bonnefond, François, Cambien, John C., Chamber, Francesco, Cucca, D'Adamo, ADAMO PIO, Gail, Davie, Rudolf A., de Boer, Eco J. C., de Geu, Angela, Döring, Paul, Elliott, Jeanette, Erdmann, David M., Evan, Mario, Falchi, Wei, Feng, Aaron R., Folsom, Ian H., Frazer, Quince D., Gibson, Nicole L., Glazer, Chris, Hammond, Anna Liisa, Hartikainen, Susan R., Heckbert, Christian, Hengstenberg, Micha, Hersch, Thomas, Illig, Ruth J. F., Loo, Jennifer, Jolley, Kay Tee, Khaw, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Vasiliki, Lagou, Heather Lloyd, Jone, Thomas, Lumley, Massimo, Mangino, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Yasin, Memari, Braxton D., Mitchell, Grant W., Montgomery, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ute, Nöthling, Ilja M., Nolte, David J., Porteou, Anneli, Pouta, Peter P., Pramstaller, Janne, Pullat, Susan M., Ring, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Nilesh J., Samani, Jennifer, Sambrook, David, Schlessinger, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Nicholas L., Smith, Harold, Snieder, John M., Starr, Michael, Stumvoll, Atsushi, Takahashi, W. H., Wilson Tang, Kent, Taylor, Albert, Tenesa, Swee Lay, Thein, Anke, Tönje, Manuela, Uda, Sheila, Ulivi, Dirk J., van Veldhuisen, Peter M., Visscher, Uwe, Völker, H., Erich Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Tsun Po, Yang, Jing Hua, Zhao, Paavo, Zitting, John R., Bradley, George V., Dedoussi, Gasparini, Paolo, Stanley L., Hazen, Andres, Metspalu, Mario, Pirastu, Alan R., Shuldiner, L., Joost van Pelt, Jaap Jan, Zwaginga, Dorret I., Boomsma, Ian J., Deary, Andre, Franke, Philippe, Froguel, Santhi K., Ganesh, Marjo Riitta, Jarvelin, Nicholas G., Martin, Christa, Meisinger, Bruce M., Psaty, Timothy D., Spector, Nicholas J., Wareham, Jan Willem N., Akkerman, Marina, Ciullo, Panos, Delouka, Andreas, Greinacher, Steve, Jupe, Naoyuki, Kamatani, Jyoti, Khadake, Jaspal S., Kooner, Josef, Penninger, Inga, Prokopenko, Derek, Stemple, Daniela, Toniolo, Lorenz, Wernisch, Serena, Sanna, Andrew A., Hick, Augusto, Rendon, Manuel A., Ferreira, Willem H., Ouwehand, Nicole, Soranzo, Faculteit Medische Wetenschappen/UMCG, Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Life Course Epidemiology (LCE), Biological Psychology, EMGO+ - Mental Health, Landsteiner Laboratory, and Clinical Haematology

Subjects
Blood Platelets, Netherlands Twin Register (NTR), BLOOD, Transcription, Genetic, Population, LOCI, Genome-wide association study, Genomics, 030204 cardiovascular system & hematology, Biology, HEMATOPOIESIS, Article, 03 medical and health sciences, 0302 clinical medicine, Animals, Drosophila Proteins, Humans, Gene silencing, Gene Silencing, Protein Interaction Maps, GENOME-WIDE ASSOCIATION, education, Gene, Zebrafish, POPULATION, Cell Size, 030304 developmental biology, Megakaryopoiesis, Genetics, platelet, 0303 health sciences, education.field_of_study, Multidisciplinary, Genome, Human, Platelet Count, Gene Expression Profiling, Zebrafish Proteins, Europe, Gene expression profiling, DROSOPHILA, Drosophila melanogaster, Human genome, Megakaryocytes, Genome-Wide Association Study
Abstract

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. © 2011 Macmillan Publishers Limited. All rights reserved.

Published
2011
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