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1. Best practice data life cycle approaches for the life sciences [version 2; referees: 2 approved]

Author

Philippa C. Griffin, Jyoti Khadake, Kate S. LeMay, Suzanna E. Lewis, Sandra Orchard, Andrew Pask, Bernard Pope, Ute Roessner, Keith Russell, Torsten Seemann, Andrew Treloar, Sonika Tyagi, Jeffrey H. Christiansen, Saravanan Dayalan, Simon Gladman, Sandra B. Hangartner, Helen L. Hayden, William W.H. Ho, Gabriel Keeble-Gagnère, Pasi K. Korhonen, Peter Neish, Priscilla R. Prestes, Mark F. Richardson, Nathan S. Watson-Haigh, Kelly L. Wyres, Neil D. Young, and Maria Victoria Schneider

Subjects
Opinion Article, Articles, Data Sharing, data sharing, data management, open science, bioinformatics, reproducibility
Abstract

Throughout history, the life sciences have been revolutionised by technological advances; in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a ‘life cycle’ view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain. Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on ‘omics’ datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.

Published
2018
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2. Best practice data life cycle approaches for the life sciences [version 1; referees: 2 approved with reservations]

Author

Philippa C. Griffin, Jyoti Khadake, Kate S. LeMay, Suzanna E. Lewis, Sandra Orchard, Andrew Pask, Bernard Pope, Ute Roessner, Keith Russell, Torsten Seemann, Andrew Treloar, Sonika Tyagi, Jeffrey H. Christiansen, Saravanan Dayalan, Simon Gladman, Sandra B. Hangartner, Helen L. Hayden, William W.H. Ho, Gabriel Keeble-Gagnère, Pasi K. Korhonen, Peter Neish, Priscilla R. Prestes, Mark F. Richardson, Nathan S. Watson-Haigh, Kelly L. Wyres, Neil D. Young, and Maria Victoria Schneider

Subjects
Opinion Article, Articles, Data Sharing, data sharing, data management, open science, bioinformatics, reproducibility
Abstract

Throughout history, the life sciences have been revolutionised by technological advances; in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a ‘life cycle’ view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain. Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on ‘omics’ datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.

Published
2017
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3. The MIntAct project - IntAct as a common curation platform for 11 molecular interaction databases.

Author

Sandra E. Orchard, Mais G. Ammari, Bruno Aranda, Lionel Breuza, Leonardo Briganti, Fiona Broackes-Carter, Nancy H. Campbell, Gayatri Chavali, Carol Chen, Noemi del-Toro, Margaret J. Duesbury, Marine Dumousseau, Eugenia Galeota, Ursula Hinz, Marta Iannuccelli, Sruthi Jagannathan, Rafael C. Jiménez, Jyoti Khadake, Astrid Lægreid, Luana Licata, Ruth C. Lovering, Birgit Meldal, Anna N. Melidoni, Mila Milagros, Daniele Peluso, Livia Perfetto, Pablo Porras, Arathi Raghunath, Sylvie Ricard-Blum, Bernd Roechert, Andre Stutz, Michael Tognolli, Kim Van Roey, Gianni Cesareni, and Henning Hermjakob

Published
2014
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4. The IntAct molecular interaction database in 2012.

Author

Samuel Kerrien, Bruno Aranda, Lionel Breuza, Alan J. Bridge, Fiona Broackes-Carter, Carol Chen, Margaret J. Duesbury, Marine Dumousseau, Marc Feuermann, Ursula Hinz, Christine Jandrasits, Rafael C. Jiménez, Jyoti Khadake, Usha Mahadevan, Patrick Masson, Ivo Pedruzzi, Eric Pfeiffenberger, Pablo Porras, Arathi Raghunath, Bernd Roechert, Sandra E. Orchard, and Henning Hermjakob

Published
2012
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5. The IntAct molecular interaction database in 2010.

Author

Bruno Aranda, P. Achuthan, Yasmin Alam-Faruque, Irina M. Armean, Alan J. Bridge, C. Derow, Marc Feuermann, A. T. Ghanbarian, Samuel Kerrien, Jyoti Khadake, Jules Kerssemakers, C. Leroy, Michael P. Menden, Magali Michaut, Luisa Montecchi-Palazzi, S. N. Neuhauser, Sandra E. Orchard, V. Perreau, Bernd Roechert, K. van Eijk, and Henning Hermjakob

Published
2010
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6. IntAct - open source resource for molecular interaction data.

Author

Samuel Kerrien, Yasmin Alam-Faruque, Bruno Aranda, I. Bancarz, Alan J. Bridge, C. Derow, Emily Dimmer, Marc Feuermann, A. Friedrichsen, Rachael P. Huntley, C. Kohler, Jyoti Khadake, C. Leroy, A. Liban, C. Lieftink, Luisa Montecchi-Palazzi, Sandra E. Orchard, Judith E. Risse, Karine Robbe, Bernd Roechert, David Thorneycroft, Y. Zhang, Rolf Apweiler, and Henning Hermjakob

Published
2007
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7. Regulatory elements associated with paternally-expressed genes in the imprinted murine Angelman/Prader-Willi syndrome domain.

Author

Sara Rodriguez-Jato, Jixiu Shan, Jyoti Khadake, Arnold D Heggestad, Xiaojie Ma, Karen A Johnstone, James L Resnick, and Thomas P Yang

Subjects
Medicine, Science
Abstract

The Angelman/Prader-Willi syndrome (AS/PWS) domain contains at least 8 imprinted genes regulated by a bipartite imprinting center (IC) associated with the SNRPN gene. One component of the IC, the PWS-IC, governs the paternal epigenotype and expression of paternal genes. The mechanisms by which imprinting and expression of paternal genes within the AS/PWS domain - such as MKRN3 and NDN - are regulated by the PWS-IC are unclear. The syntenic region in the mouse is organized and imprinted similarly to the human domain with the murine PWS-IC defined by a 6 kb interval within the Snrpn locus that includes the promoter. To identify regulatory elements that may mediate PWS-IC function, we mapped the location and allele-specificity of DNase I hypersensitive (DH) sites within the PWS-IC in brain cells, then identified transcription factor binding sites within a subset of these DH sites. Six major paternal-specific DH sites were detected in the Snrpn gene, five of which map within the 6 kb PWS-IC. We postulate these five DH sites represent functional components of the murine PWS-IC. Analysis of transcription factor binding within multiple DH sites detected nuclear respiratory factors (NRF's) and YY1 specifically on the paternal allele. NRF's and YY1 were also detected in the paternal promoter region of the murine Mrkn3 and Ndn genes. These results suggest that NRF's and YY1 may facilitate PWS-IC function and coordinately regulate expression of paternal genes. The presence of NRF's also suggests a link between transcriptional regulation within the AS/PWS domain and regulation of respiration. 3C analyses indicated Mkrn3 lies in close proximity to the PWS-IC on the paternal chromosome, evidence that the PWS-IC functions by allele-specific interaction with its distal target genes. This could occur by allele-specific co-localization of the PWS-IC and its target genes to transcription factories containing NRF's and YY1.

Published
2013
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8. Transcript specific regulation of expression influences susceptibility to multiple sclerosis

Author

M. Fraser, Stephen Sawcer, Joanne L. Jones, Wenjia Liao, John Thorpe, Maria Ban, Alastair Compston, Amie Baker, Jyoti Khadake, Alasdair Coles, Paul Molyneux, Jones, Joanne [0000-0003-4974-1371], and Apollo - University of Cambridge Repository

Subjects
Genetics, Adult, 0303 health sciences, Linkage disequilibrium, Multiple Sclerosis, Polymorphism, Genetic, 030305 genetics & heredity, Genome-wide association study, Biology, Middle Aged, Genome, 03 medical and health sciences, Adaptor Proteins, Vesicular Transport, Open Reading Frames, Transcription (biology), Regulatory sequence, Gene expression, Humans, Genetic Predisposition to Disease, RNA, Messenger, Gene, Genetics (clinical), Alleles, Genetic association
Abstract

Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10-24). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.

Published
2020

9. 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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10. Further studies of the down-regulation by Factor I of the C3b feedback cycle using endotoxin as a soluble activator and red cells as a source of CR1 on sera of different complotype

Author

David J. Seilly, Anna Buchberger, Elizabeth Lay, Wilhelm J. Schwaeble, Peter J. Lachmann, and Jyoti Khadake

Subjects
Adult, Lipopolysaccharides, 0301 basic medicine, medicine.medical_specialty, Erythrocytes, Adolescent, Immunology, Population, Hemoglobinuria, Paroxysmal, Down-Regulation, Complement factor I, Biology, Antibodies, Monoclonal, Humanized, Young Adult, 03 medical and health sciences, Gene Frequency, Internal medicine, medicine, Humans, Immunology and Allergy, education, Allele frequency, Aged, education.field_of_study, Polymorphism, Genetic, Activator (genetics), Immune Sera, Age Factors, Original Articles, Middle Aged, Eculizumab, Complement system, 030104 developmental biology, Endocrinology, Complement Factor I, Complement Factor H, Factor H, Complement C3b, Receptors, Complement 3b, iC3b, medicine.drug
Abstract

Summary In this paper we have extended our earlier studies of the action of increasing Factor I concentration on complement activation by using a soluble activator, lipopolysaccharide (LPS) endotoxin, and using human erythrocytes as a source of CR1 – the co-factor needed for the final clip of iC3b to C3dg by Factor I. Using this more physiological system, the results show that we can predict that a quite modest increase in Factor I concentration – 22 µg/ml of extra Factor I – will convert the activity of the highest risk sera to those of the lowest risk. Preliminary experiments have been performed with erythrocytes allotyped for CR1 number. While we have not been able to perform an adequate study of their co-factor activities in our assays, preliminary experiments suggest that when Factor I levels are increased the difference produced by different allotypes of red cells is largely overcome. This suggests that in patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with eculizumab, additional treatment with Factor I may be very useful in reducing the need for blood transfusion. We have also explored the age-related allele frequency for the two polymorphisms of Factor H and the polymorphism of C3. In our population, unlike the 1975 study, we found no age variation in the allele frequency in these polymorphisms. This may, however, reflect that the Cambridge BioResource volunteers do not include many very young or very elderly patients, and in general comprise a population not greatly at risk of death from infectious disease.

Published
2015
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11. Low frequency and rare coding variation contributes to multiple sclerosis risk

Author

Fredrik Karpe, Graeme Stewart, Jan Hillert, Elisabetta Mascia, Matt J. Neville, Verena Grummel, Jonathan L. Haines, Kate Fitzgerald, Bernhard Hemmer, Julia Y Mescheriakova, Benedicte A. Lie, Efthimios Luessi, Federica Esposito, Andreas Ziegler, Ioanna Konidari, Cristin McCabe, Keith R. Edwards, Roland Martin, Daniele Cusi, Elisabeth Gulowsen Celius, Cristina Agliardi, Anne Spurkland, Georgios M. Hadjigeorgiou, Lena Guillot-Noel, Antonios Bayas, Uwe K. Zettl, Kjell-Morten Myhr, Maria Ban, Rogier Q. Hintzen, Frauke Zipp, Mireia Sospedra, Till F. M. Andlauer, Adrian J. Ivinson, Mary F. Davis, Mark Lathrop, Daniela Galimberti, Pierre-Antoine Gourraud, Genevieve Lachance, Bruce A.C. Cree, Robin Lemmens, Ashley Beecham, Steffan D. Bos, Bruce V. Taylor, Maurizio Leone, Manuel Comabella, Maja Jagodic, Helle Bach Søndergaard, David A. Hafler, Ingrid Kockum, Nadia Barizzone, Ralf Gold, Tania Kümpfel, Per Soelberg Sørensen, Seema Kalra, An Goris, Philip Van Damme, Marie B. D'hooghe, Cathy Schaefer, Efthimios Dardiotis, Alastair Compston, Lotti Tajoori, Sandra D'Alfonso, Ilijas Jelcic, Stephen Sawcer, Brigitte Wildemann, Friedemann Paul, Lise Wegner Thoerner, Silvia Delgado, Tomas Olsson, Mitja Mitrovic, Hayrettin Tumani, Henrik Ullum, Lisa F. Barcellos, Xavier Montalban, Ellen Lathi, Finn Sellebjerg, Thomas Werge, Christina M. Lill, Pernilla Stridh, Paul I.W. de Bakker, Cornelia M. van Duijn, Jyoti Khadake, Jac Charlesworth, Melissa Sorosina, Christiane Gasperi, Stephen L. Hauser, Anne H. Cross, Isabelle Cournu-Rebeix, Nikolaos A. Patsopoulos, Fredrik Piehl, Lars Alfredsson, Bertrand Fontaine, Marieme Dembele, Margaret A. Pericak-Vance, Janna Saarela, Ulf Ziemann, Annette Bang Oturai, Stacy J. Caillier, Jorge R. Oksenberg, Bénédicte Dubois, Björn Tackenberg, Christoph Heesen, Jacob L. McCauley, Florian Then Bergh, Clemens Warnke, Sergio E. Baranzini, Peter A. Calabresi, Chris Cotsapas, Clive Hawkins, Martin Stangel, Hakon Hakonarson, Sandra Vukusik, Christiane Graetz, Heinz Wiendl, Howard L. Weiner, Laura Piccio, Giancarlo Comi, Ralf A. Linker, Luisa Bernardinelli, Cristoforo Comi, Filippo Martinelli-Boneschi, Hanne F. Harbo, Dorothea Buck, Clara P. Manrique, David R. Booth, Benjamin Knier, Philip L. De Jager, Viola Pongratz, Laura Ferrè, Vincent Damotte, Adam Santaniello, Theresa Dankowski, and Pirro G. Hysi

Subjects
Genetics, 0303 health sciences, Linkage disequilibrium, Multiple sclerosis, Disease, Biology, Heritability, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Epistasis, Coding region, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

Multiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common variant signals, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

Published
2018
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12. Genome-wide meta-analysis of cognitive empathy: Heritability, and correlates with sex, neuropsychiatric conditions and cognition

Author

Dorret I. Boomsma, Gitta H. Lubke, E. Mawbey-Adamson, Varun Warrier, Nadia K. Litterman, Nicholas G. Martin, Thomas Bourgeron, Katrina L. Grasby, S. E. Medland, David A. Hinds, J-J Hottenga, Florina Uzefovsky, Roberto Toro, Jyoti Khadake, Peter K. Smith, Bhismadev Chakrabarti, Simon Baron-Cohen, Peter K. Hatemi, VU University medical center, University of Cambridge [UK] (CAM), QIMR Berghofer Medical Research Institute, Ben-Gurion University of the Negev (BGU), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Reading (UOR), Cambridge University Hospitals - NHS (CUH), 23andMe Inc., Vrije Universiteit Amsterdam [Amsterdam] (VU), VU University Medical Center [Amsterdam], University of Notre Dame [Indiana] (UND), Pennsylvania State University (Penn State), Penn State System, Cambridgeshire & Peterborough NHS Foundation Trust [Cambridge] (CPFT), This study was funded by grants from the Templeton World Charity Foundation, Inc., the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Institut Pasteur, the CNRS and the University Paris Diderot. V.W. is funded by St John’s College, Cambridge, and Cambridge Commonwealth Trust. The research was carried out in association with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East of England at Cambridgeshire and Peterborough NHS Foundation Trust. The research was supported by the National Human Genome Research Institute of the National Institutes of Health (grant number R44HG006981). The National Science Foundation (grant numbers 0729493 and 0721707) supported the research on the Brisbane Longitudinal Twin Study. F.U. was supported by the British Friends of Haifa University, the Israel Science Foundation (grant no. 449/14), the British Friends of Hebrew University and the Joseph Levy Charitable Foundation. T.B. was supported by the Institut Pasteur, the University Paris Diderot, CNRS, and the Bettencourt-Schueller Foundation. We acknowledge with gratitude the generous support of Drs Dennis and Mireille Gillings in strengthening the collaboration between SBC and TB, and between Cambridge University and the Institut Pasteur. This publication was made possible through the support of a grant from the Templeton World Charity Foundation, Inc., We thank the research participants and employees of 23andMe for making this work possible. We also thank the volunteers of the Brisbane Longitudinal Twin Study and the NIHR Cambridge BioResource. Finally, we thank Silviu-Alin Bacanu, Hilary Finucane, Brendan Bulik-Sullivan, Carrie Allison, Michael Lombardo and Richard Bethlehem for helpful discussions., Gènes, Synapses et Cognition, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Mental Health, Baron-Cohen, Simon [0000-0001-9217-2544], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, 0301 basic medicine, Netherlands Twin Register (NTR), Anorexia Nervosa, [SDV]Life Sciences [q-bio], Twins, Library science, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SCCO]Cognitive science, Cognition, Sex Factors, Sex factors, Journal Article, Humans, Genetic Predisposition to Disease, Sociology, 10. No inequality, Molecular Biology, Aged, Extramural, Hebrew, Mental Disorders, Middle Aged, Medical research, language.human_language, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Meta-analysis, Cognitive empathy, language, Commonwealth, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Empathy, SDG 4 - Quality Education, Genome-Wide Association Study
Abstract

This study was funded by grants from the Templeton World Charity Foundation, Inc., the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Institut Pasteur, the CNRS and the University Paris Diderot. VW is funded by St. John’s College, Cambridge, and Cambridge Commonwealth Trust. The research was carried out in association with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East of England at Cambridgeshire and Peterborough NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Human Genome Research Institute of the National Institutes of Health (grant number R44HG006981). The National Science Foundation (grant numbers 0729493 and 0721707) supported the research on the Brisbane Longitudinal Twin Study. FU was supported by the British Friends of Haifa University, the Israel Science Foundation (grant no. 449/14), the British Friends of Hebrew University, and the Joseph Levy Charitable Foundation. TB was supported by the Institut Pasteur and the Bettencourt-Schueller Foundation. We thank the research participants and employees of 23andMe for making this work possible. We also thank the volunteers of the Brisbane Longitudinal Twin Study and the NIHR Cambridge BioResource.

Published
2018
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13. Best Practice Data Life Cycle Approaches for the Life Sciences

Author

Neil D. Young, Andrew Treloar, Simon Gladman, Sandra Hangartner, Bernard J. Pope, Peter Neish, Helen L. Hayden, Mark F. Richardson, Jyoti Khadake, Saravanan Dayalan, Jeffrey H. Christiansen, Gabriel Keeble-Gagnère, Sonika Tyagi, Nathan S. Watson-Haigh, Maria Victoria Schneider, Torsten Seemann, Priscilla R. Prestes, Ute Roessner, Suzanna E. Lewis, Philippa C. Griffin, William Ho, Andrew J Pask, Pasi K. Korhonen, Sandra Orchard, Keith Russell, Kelly L. Wyres, and Kate S. LeMay

Subjects
0301 basic medicine, Open science, Data Sharing, Test data generation, Best practice, Data management, Physiology, Biology, Space (commercial competition), General Biochemistry, Genetics and Molecular Biology, Domain (software engineering), 03 medical and health sciences, 0302 clinical medicine, open science, Instrumentation (computer programming), General Pharmacology, Toxicology and Pharmaceutics, reproducibility, 030304 developmental biology, 0303 health sciences, Data processing, General Immunology and Microbiology, business.industry, General Medicine, Articles, bioinformatics, Opinion Article, Data life cycle, Data science, Data sharing, Open data, 030104 developmental biology, data management, business, 030217 neurology & neurosurgery
Abstract

Throughout history, the life sciences have been revolutionised by technological advances; in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a ‘life cycle’ view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain.Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on ‘omics’ datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.

Published
2017
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14. The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility

Author

Ashley Beecham, David A. Hafler, Colombe J, Ublick K, Stephen Sawcer, Marcus C. S. Lee, Adam Santaniello, An Goris, Frank Seibold, Xavier Montalban, G. Comi, Christiane Gasperi, Sandra D'Alfonso, Federica Esposito, Laurent Peyrin-Biroulet, Frauke Zipp, Ioanna Konidari, Elisabeth Gulowsen Celius, Achim Berthele, Amoroso A, Rogier Q. Hintzen, Johan Van Limbergen, Marieme Dembele, Fredrik Karpe, Zhang W, Robbins A, Moiola L, Annette Bang Oturai, Cristin McCabe, Filippo Martinelli-Boneschi, M Lindén, Keith R Edwards, Hanne F. Harbo, Zuccalà M, Marc Lémann, Felix Luessi, Noriko Isobe, Nadia Barizzone, Renata D'Incà, Croft A, Ioannis S. Vlachos, Frohlich I, Martinelli, Daniela Galimberti, Efthimios Dardiotis, Lisa F. Barcellos, Brendan T. Keenan, Maja Jagodic, Ferdinando Clarelli, Bénédicte Dubois, Nicholas A. Kennedy, Lohith Madireddy, Grant W. Montgomery, Tommy Olsson, Phil De Jager, Lo A, Peter A. Calabresi, Brandes A, Chris Cotsapas, Bakker Pd, Steffan D. Bos, Christina M. Lill, Karban A, Thoerner Lw, Tojo James, Wong G, Harald Peeters, M.-M. Hoshi, Roberts R, Fredrik Piehl, Lars Alfredsson, Giorgos M. Hadjigeorgiou, Bertrand Fontaine, Melissa Sorosina, Benedetti M, Maria Ban, Jorge R. Oksenberg, Howard L. Weiner, Ingrid Kockum, Mireia Sospedra, Taylor Km, Henrik Ullum, Izaura Lima Bomfim, Stronati L, Molyneux P, Replogle J, Stacy J. Caillier, Zhang H, Till F. M. Andlauer, Margaret A. Pericak-Vance, Jan Hillert, Luisa Bernardinelli, Taibo Li, Helle Bach Søndergaard, Ilijas Jelcic, Nikolaos A. Patsopoulos, Silvia Delgado, Cathy Schaefer, Thomas Korn, Laura Piccio, Mark Mühlau, Deborah D. Proctor, B. Hemmer, Elizabeth M. Bradshaw, Hysi P, Megan C Neville, Mary F. Davis, Dorlan J. Kimbrough, Jyoti Khadake, Jean-Pierre Hugot, David Gomez-Cabrero, Murray L. Barclay, Anne H. Cross, Kasper Lage, Stephen L. Hauser, A Compston, Zimmer A, Ivinson A, Anne Spurkland, Jonas Halfvarson, Charles C. White, Biberacher, Zarzycki O, Kathryn C. Fitzgerald, Finn Sellebjerg, Ellis Patrick, Andrea Zauli, Bruce V. Taylor, Maurizio Leone, Genevieve Lachance, Marta Olah, B. Cree, Manuel Comabella, Arie Levine, Domizia Vecchio, Mathias Chamaillard, Mark Lathrop, Clara Guaschino, Roland Martin, Hanigan K, Pierre-Antoine F. D. Gourraud, Maria Cimpean, Jonathan L. Haines, Dorothea Buck, Marco Salvetti, Per Soelberg Sørensen, Noel Lg, Mitja Mitrovic, Graeme J. Stewart, Benjamin Knier, Ellen Lathi, Cottone M, Laura Ferrè, Winn P, Duijn Cv, Monica Milla, Tune H. Pers, I. Oikonomou, An D, David R. Booth, Rebeix Ic, Clara P. Manrique, Massey D, Evelyn Ng Sm, Törkvist L, Daniele Cusi, Shoostari P, Vatn Mh, Paola Cavalla, Silvia Santoro, Gossum Av, Seema Kalra, Paul Rutgeerts, Clive Hawkins, Sandra Vukusik, Khan Ma, Hakon Hakonarson, Paul Henderson, Christiane Graetz, Julia Y Mescheriakova, Jean-François Rahier, Panteliadis I, Cristina Agliardi, Grummel, Jacob L. McCauley, Amie Baker, Janna Saarela, Sergio E. Baranzini, J W Thorpe, and Damotte

Subjects
0303 health sciences, Microglia, Multiple sclerosis, Central nervous system, Biology, medicine.disease, Major histocompatibility complex, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine.anatomical_structure, Autoimmune Process, Immunology, medicine, biology.protein, Gene, 030217 neurology & neurosurgery, X chromosome, 030304 developmental biology
Abstract

We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain - resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.One Sentence Summary:We report a detailed genetic and genomic map of multiple sclerosis, and describe the role of putatively affected genes in the peripheral immune system and brain resident microglia.

Published
2017

15. A Meta-Analysis of Cognitive Empathy: Heritability and Correlates of the ‘Reading the Mind in the Eyes’ Test with Psychiatric Conditions, Psychological Traits and Subcortical Volumes

Author

Katrina L. Grasby, Bhismadev Chakrabarti, Paula Smith, Nicholas G. Martin, Simon Baron-Cohen, Florina Uzefovsky, David A. Hinds, Eleanor Mawbey-Adamson, Peter K. Hatemi, Sarah E. Medland, Nadia K. Litterman, Jouke-Jan Hottenga, Gitta H. Lubke, Varun Warrier, Thomas Bourgeron, Jyoti Khadake, Roberto Toro, and Dorret I. Boomsma

Subjects
medicine.medical_specialty, media_common.quotation_subject, Developmental psychology, 03 medical and health sciences, 0302 clinical medicine, Social cognition, Theory of mind, medicine, 0501 psychology and cognitive sciences, Pharmacology (medical), Psychiatry, Biological Psychiatry, media_common, Pharmacology, 05 social sciences, Heritability, Genetic architecture, Test (assessment), Psychiatry and Mental health, Neurology, Mentalization, Feeling, Meta-analysis, Neurology (clinical), Psychology, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract

Background Cognitive empathy is the ability to recognize or imagine another person’s mental states, such as their thoughts, intentions, desires, goals, and feelings. Cognitive empathy (also known as ‘theory of mind’ or ‘mentalizing’) is distinct from affective empathy, which is the drive to respond to another’s mental state with an appropriate emotion. Cognitive empathy has been linked to several psychiatric conditions, but little is known about its genetic architecture. Methods We conducted genome-wide association studies of cognitive empathy using the ‘Reading the Mind in the Eyes’ Test (Eyes test) in 88,056 research participants with European ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1,581 participants with European ancestry (939 females and 642 males) from the Australian Twin Registry. In addition, we quantified the heritability explained by all variants, and calculated genetic correlations between scores on the Eyes test and various traits. Results We confirmed a female advantage on the Eyes Test (Cohen’s d = 0.21, P Discussion Our study highlights the genetic contributions of social cognition and its relation to psychological traits and subcortical brain volumes. In particular, we show that variants that contribute to Eyes test also contribute to volumes of the striatum, implicating these regions in cognitive empathy. We also show that some of the phenotypic sex differences can be attributed to differences in genetic architecture between males and females for the Eyes test. Delineating how these different genetic architectures interact with sex-specific biological pathways will help elucidate the mechanisms that underlie biological sex-difference for the Eyes test.

Published
2017
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16. The MIntAct project - IntAct as a common curation platform for 11 molecular interaction databases

Author

Livia Perfetto, Lionel Breuza, Rafael C. Jimenez, Anna N. Melidoni, Gayatri Chavali, Arathi Raghunath, Carol Chen, Marta Iannuccelli, Michael Tognolli, Daniele Peluso, Sylvie Ricard-Blum, Sandra Orchard, Andre Stutz, Eugenia Galeota, Ruth C. Lovering, Bernd Roechert, Astrid Lagreid, Margaret Duesbury, Jyoti Khadake, Fiona Broackes-Carter, Ursula Hinz, Nancy H. Campbell, Leonardo Briganti, Birgit H M Meldal, Gianni Cesareni, Noemi del-Toro, Sruthi Jagannathan, Henning Hermjakob, Marine Dumousseau, Mais G. Ammari, Kim Van Roey, Mila Milagros, Pablo Porras, Luana Licata, and Bruno Aranda

Subjects
ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, Data_CODINGANDINFORMATIONTHEORY, Biology, computer.software_genre, II. Protein sequence and structure, motifs and domains, Databases, Protein Interaction Mapping, Genetics, Databases, Protein, Internet, Data curation, Database, Software, Extramural, business.industry, Protein, Binding (Molecular Function), Genus Mentha, Settore BIO/18 - Genetica, Open data, ComputingMethodologies_PATTERNRECOGNITION, Data_GENERAL, The Internet, business, Merge (version control), computer
Abstract

IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org). This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You are not required to obtain permission to reuse this article.

Published
2014

17. Preferential condensation of SAR-DNA by histone H1 and its SPKK containing octapeptide repeat motif

Author

Jyoti Khadake and Manchanahalli R. Satyanarayana Rao

Subjects
Molecular Sequence Data, Biophysics, Scaffold associated region, Biology, Biochemistry, Histones, Poly dA-dT, Histone H1, Structural Biology, Histone H2A, Histone methylation, Genetics, Animals, AT-hook peptide motif, Nucleosome, Histone code, Amino Acid Sequence, Histone octamer, Molecular Biology, Base Sequence, fungi, DNA, Cell Biology, Linker DNA, Peptide Fragments, Rats, Drosophila melanogaster, Oligodeoxyribonucleotides, Histone methyltransferase
Abstract

Linker histone H1 binds preferentially the scaffold associated region (SAR) DNA elements that contain characteristic oligo dA·dT tracts. In the present study, we have compared the condensation brought about by histone H1 of a SAR DNA fragment in the histone spacer region of Drosophila melanogaster with that of a random DNA (pBR322 EcoRI-SalI) fragment by circular dichroism spectroscopy. The condensation of the SAR DNA fragment by histone H1 is 3–4-fold higher than that of the random DNA fragment. A 16-mer peptide, ATPKKSTKKTPKKAKK, the sequence that is present in the C-terminus of histone H1d, which has recently been shown to possess DNA and chromatin condensing properties, also condenses the SAR DNA fragment preferentially in a highly cooperative manner. We have proposed a model for the dynamics of chromatin structure involving histone H1-SAR DNA interaction through SPKK containing peptide motifs and its competition by AT-hook peptides present in the nonhistone chromosomal proteins like HMG-I and HMG-Y.

Published
1997
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18. Protein interaction data curation: the International Molecular Exchange (IMEx) consortium

Author

Arathi Raghunath, Bernd Roechert, Robert E. W. Hancock, Emilie Chautard, Carol Chen, Sandra Orchard, Sara Abbani, Bruno Aranda, Alan Bridge, Samuel Kerrien, Volker Stümpflen, Livia Perfetto, Andrew Chatr-aryamontri, Usha Mahadevan, Shelby L. Bidwell, Peter Uetz, Johannes B. Goll, Marine Dumousseau, Igor Jurisica, David J. Lynn, Jignesh Bhate, Leonardo Briganti, Gianni Cesareni, Mike Tyers, Sylvie Ricard-Blum, Ioannis Xenarios, Lukasz Salwinski, Henning Hermjakob, Jyoti Khadake, Fiona S. L. Brinkman, and Linda Hannick

Subjects
Quality Control, Service (systems architecture), Computer science, Bioinformatics, Biochemistry, Article, World Wide Web, 03 medical and health sciences, Databases, 0302 clinical medicine, Protein Interaction Mapping, Databases, Protein, Molecular Biology, 030304 developmental biology, 0303 health sciences, Periodicals as Topic, Proteins, Protein Binding, Data curation, Proteins/chemistry, Proteins/metabolism, Extramural, Protein, Cell Biology, Settore BIO/18 - Genetica, Proteins metabolism, Search interface, 030217 neurology & neurosurgery, Biotechnology, Molecular exchange
Abstract

The International Molecular Exchange (IMEx) consortium is an international collaboration between major public interaction data providers to share literature-curation efforts and make a nonredundant set of protein interactions available in a single search interface on a common website (http://www.imexconsortium.org/). Common curation rules have been developed, and a central registry is used to manage the selection of articles to enter into the dataset. We discuss the advantages of such a service to the user, our quality-control measures and our data-distribution practices.

Published
2012

19. PSICQUIC and PSISCORE: accessing and scoring molecular interactions

Author

Hagen Blankenburg, Ruth Isserlin, Samuel Kerrien, David Eisenberg, Rafael C. Jimenez, Jyoti Khadake, Johannes B. Goll, Arnaud Ceol, Marine Dumousseau, Sandra Orchard, Jose M. Dana, Guanming Wu, Henning Hermjakob, Mario Albrecht, Sabry Razick, Keiichiro Ono, Bruno Aranda, Ian Donaldson, John P. Overington, Emilie Chautard, Milan Simonovic, Robert E. W. Hancock, Sameer Velankar, Gary D. Bader, Gavin O'Kelly, Gianni Cesareni, Mike Tyers, Olga Rigina, Magali Michaut, Javier De Las Rivas, Sylvie Ricard-Blum, Gerard J. Kleywegt, Anna Gaulton, Andrew G. Winter, Lukasz Salwinski, David J. Lynn, Carlos Prieto, Fiona S. L. Brinkman, Jules Kerssemakers, and Eugenia Galeota

Subjects
Chemical and physical biology [NCMLS 7], Genetics and epigenetic pathways of disease [NCMLS 6], Databases, Factual, Context (language use), Computational biology, Biology, Proteomics, Biochemistry, Article, 03 medical and health sciences, Animals, Software, Humans, Proteins, Computational Biology, Protein Binding, Databases, Molecular Biology, Factual, 030304 developmental biology, 0303 health sciences, Molecular interactions, 030302 biochemistry & molecular biology, A protein, Cell Biology, 3. Good health, Settore BIO/18 - Genetica, Proteins metabolism, Biotechnology
Abstract

To the Editor.-- Author Manuscript.-- et al., This study was supported by the European Commission under the Serving Life-science Information for the Next Generation contract 226073; Proteomics Standards Initiative and International Molecular Exchange contract FP7-HEALTH-2007-223411; Apoptosis Systems Biology Applied to Cancer and AIDS contract FP7-HEALTH-2007-200767; Experimental Network for Functional Integration contract LSHG-CT-2005-518254; German National Genome Research Network; German Research Foundation contract KFO 129/1-2; US National Institutes of Health grant R01GM071909; the Italian Association for Cancer Research; a Wellcome Trust Strategic Award to the European Molecular Biology Laboratory–European Bioinformatics Institute for Chemogenomics Databases; Grand Challenges in Global Health Research, the Canadian Institutes of Health Research, Foundation for the National Institutes of Health and Genome British Columbia; and a German Research Foundation–funded Cluster of Excellence for Multimodal Computing and Interaction.

Published
2011

20. The IntAct molecular interaction database in 2010

Author

Sandra Orchard, Henning Hermjakob, M Feuermann, P. Achuthan, Jyoti Khadake, K. van Eijk, Luisa Montecchi-Palazzi, Michael P. Menden, Avazeh T. Ghanbarian, Alan Bridge, Yasmin Alam-Faruque, Bernd Roechert, Victoria M. Perreau, Bruno Aranda, Irina M. Armean, C. Leroy, C. Derow, Samuel Kerrien, J. Kerssemakers, S. N. Neuhauser, and Magali Michaut

Subjects
Chemical and physical biology [NCMLS 7], Source code, Genetics and epigenetic pathways of disease [NCMLS 6], media_common.quotation_subject, Information Storage and Retrieval, Biology, computer.software_genre, User-Computer Interface, 03 medical and health sciences, Annotation, 0302 clinical medicine, Software, Databases, Genetic, Protein Interaction Mapping, Controlled vocabulary, Genetics, Animals, Humans, False Positive Reactions, Zoom, Databases, Protein, 030304 developmental biology, media_common, Internet, 0303 health sciences, Database, business.industry, Computational Biology, Proteins, Articles, Protein Structure, Tertiary, Open data, Vocabulary, Controlled, 030220 oncology & carcinogenesis, Programming Languages, The Internet, business, computer, Level of detail
Abstract

Contains fulltext : 185558.pdf (Publisher’s version ) (Open Access) IntAct is an open-source, open data molecular interaction database and toolkit. Data is abstracted from the literature or from direct data depositions by expert curators following a deep annotation model providing a high level of detail. As of September 2009, IntAct contains over 200.000 curated binary interaction evidences. In response to the growing data volume and user requests, IntAct now provides a two-tiered view of the interaction data. The search interface allows the user to iteratively develop complex queries, exploiting the detailed annotation with hierarchical controlled vocabularies. Results are provided at any stage in a simplified, tabular view. Specialized views then allows 'zooming in' on the full annotation of interactions, interactors and their properties. IntAct source code and data are freely available at http://www.ebi.ac.uk/intact. 01 januari 2010

Published
2010

21. MINT and IntAct contribute to the second BioCreative challenge: serving the text-mining community with high quality molecular interaction data

Author

Andrew Chatr-aryamontri, Henning Hermjakob, Arnaud Ceol, Dave Thorneycroft, Sandra Orchard, Catherine Leroy, Cathy Derow, Jyoti Khadake, Luana Licata, Luisa Castagnoli, Bruno Aranda, Gianni Cesareni, Rolf Apweiler, Rachael P. Huntley, Samuel Kerrien, and Stefano Costa

Subjects
Societies, Scientific, Proteomics, Process (engineering), media_common.quotation_subject, Biology, Bioinformatics, computer.software_genre, Vocabulary, 03 medical and health sciences, Databases, Text mining, Controlled vocabulary, Protein Interaction Mapping, Quality (business), Bibliographic, 030304 developmental biology, media_common, 0303 health sciences, Biological data, Information retrieval, business.industry, Research, 030302 biochemistry & molecular biology, Computational Biology, Scientific, Databases, Bibliographic, Vocabulary, Controlled, Information extraction, Settore BIO/18 - Genetica, ComputingMethodologies_PATTERNRECOGNITION, Manual annotation, business, Societies, Controlled, computer
Abstract

Background In the absence of consolidated pipelines to archive biological data electronically, information dispersed in the literature must be captured by manual annotation. Unfortunately, manual annotation is time consuming and the coverage of published interaction data is therefore far from complete. The use of text-mining tools to identify relevant publications and to assist in the initial information extraction could help to improve the efficiency of the curation process and, as a consequence, the database coverage of data available in the literature. The 2006 BioCreative competition was aimed at evaluating text-mining procedures in comparison with manual annotation of protein-protein interactions. Results To aid the BioCreative protein-protein interaction task, IntAct and MINT (Molecular INTeraction) provided both the training and the test datasets. Data from both databases are comparable because they were curated according to the same standards. During the manual curation process, the major cause of data loss in mining the articles for information was ambiguity in the mapping of the gene names to stable UniProtKB database identifiers. It was also observed that most of the information about interactions was contained only within the full-text of the publication; hence, text mining of protein-protein interaction data will require the analysis of the full-text of the articles and cannot be restricted to the abstract. Conclusion The development of text-mining tools to extract protein-protein interaction information may increase the literature coverage achieved by manual curation. To support the text-mining community, databases will highlight those sentences within the articles that describe the interactions. These will supply data-miners with a high quality dataset for algorithm development. Furthermore, the dictionary of terms created by the BioCreative competitors could enrich the synonym list of the PSI-MI (Proteomics Standards Initiative-Molecular Interactions) controlled vocabulary, which is used by both databases to annotate their data content.

Published
2008

22. Recurated protein interaction datasets

Author

Luana Licata, Michael S. Livstone, David Eisenberg, David Thorneycroft, Eva Huala, Jyoti Khadake, David Botstein, Lorrie Boucher, Lukasz Salwinski, Rose Oughtred, Arnaud Ceol, Kara Dolinski, Gianni Cesareni, Mike Tyers, Henning Hermjakob, Tanya Z. Berardini, Andrew G. Winter, and Andrew Chatr Aryamontri

Subjects
Genetics, Databases, Settore BIO/18 - Genetica, Arabidopsis Proteins, Protein, MEDLINE, Databases, Protein, Cell Biology, Biology, Molecular Biology, Biochemistry, Biotechnology
Published
2009
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23. Condensation of DNA and chromatin by an SPKK-containing octapeptide repeat motif present in the C-terminus of histone H1

Author

Manchanahalli R. Satyanarayana Rao and Jyoti Khadake

Subjects
Protein Conformation, Molecular Sequence Data, Peptide, Biochemistry, Antiviral Agents, Binding, Competitive, Histones, chemistry.chemical_compound, Histone H1, Histone methylation, Histone H2A, Animals, Histone octamer, Amino Acid Sequence, chemistry.chemical_classification, biology, Circular Dichroism, Distamycins, DNA, Molecular biology, Chromatin, Peptide Fragments, Rats, Histone, chemistry, Liver, Oligodeoxyribonucleotides, biology.protein, Nucleic Acid Conformation, Peptides, Oligopeptides
Abstract

Several DNA binding motifs have been described in the C-terminus of histone H1 (Churchill & Travers, 1991), of these the S/TPKK repeat (Suzuki, 1989) often occurs as a part of an octapeptide repeat of the type XTPKKXKK. We have studied in detail the DNA and chromatin condensing properties of a consensus octapeptide KSPKKAKK (8 mer) present in many histone H1 subtypes and its imperfect repeat ATPKKSTKKTPKKAKK (16 mer TPKK) as it occurs in the C-tenminus of rat histone Hid. The 16 mer TPKK peptide containing two S/TPKK motifs was able to condense both rat oligonucleosomal (2-5 kbp) DNA and histone Hi-depleted chromatin as revealed by circular dichroism spectroscopy. The 8 mer peptide, however, was unable to condense either the DNA or the histone Hi-depleted chromatin. Both the 8 mer peptide and the 16 mer TPKK peptide displaced distamycin A from the drug-DNA complex, although with different efficiency, indicating that while these two peptides could bind DNA, only the 16 mer (TPKK) peptide could brine about condensation of DNA and histone Hi-depleted chromatin. A mutant 16 mer (TAKK) peptide wherein two proline residues are replaced by alanine, was ineffective in bringing about condensation of both DNA and histone Hi-depleted chromatin. These results suggest that the two p-turn structures present in the 16 mer (TPKK) peptide could be important in facilitating binding to different regions of duplex DNA thereby bringing about close packing and condensation. The condensation property of the 16 mer (TPKK) peptide was very similar to that of histone H1 in terms of (a) its preference for AT rich DNA, (b) cooperativity of condensation, and (c) salt dependence of condensation. The 16 mer (TPKK) peptide, but not the 8 mer peptide or the 16 mer (TAKK) peptide, could form complexes with a polynucleosomal 5S DNA core resulting in retarded mobility similar to the complexes formed with histone H1 on agarose gel electrophoresis.

Published
1997

24. Erratum: Corrigendum: Protein interaction data curation: the International Molecular Exchange (IMEx) consortium

Author

Sandra Orchard, Volker Stümpflen, Andrew Chatr-aryamontri, Fiona S. L. Brinkman, Peter Uetz, Carol Chen, Jyoti Khadake, Linda Hannick, Marine Dumousseau, Alan Bridge, Bernd Roechert, Samuel Kerrien, Livia Perfetto, Sylvie Ricard-Blum, Emilie Chautard, Usha Mahadevan, Arathi Raghunath, Ioannis Xenarios, Mike Tyers, Lukasz Salwinski, Johannes B. Goll, Robert E. W. Hancock, Igor Jurisica, Henning Hermjakob, David J. Lynn, Leonardo Briganti, Gianni Cesareni, Jignesh Bhate, Shelby L. Bidwell, Sara Abbani, and Bruno Aranda

Subjects
Data curation, health care facilities, manpower, and services, education, Cell Biology, Computational biology, Biology, Bioinformatics, Molecular Biology, Biochemistry, health care economics and organizations, Biotechnology, Molecular exchange
Abstract

Corrigendum: Protein interaction data curation: the International Molecular Exchange (IMEx) consortium

Published
2012
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25. VRK1 interacts with p53 forming a basal complex that is activated by UV-induced DNA damage

Author

Marta Vázquez-Cedeira, Jyoti Khadake, Marta Sanz-García, Inmaculada Lopez-Sanchez, Alejandro Carrillo-Jimenez, Alberto Valbuena, Pedro A. Lazo, Ministerio de Ciencia e Innovación (España), Consejo Superior de Investigaciones Científicas (España), Ministerio de Educación y Ciencia (España), European Commission, and Obra Social Kutxa

Subjects
p53, DNA Repair, Interaction, Ultraviolet Rays, DNA repair, DNA damage, Mutant, Mutation, Missense, Biophysics, Eukaryotic DNA replication, Protein Serine-Threonine Kinases, Biology, Biochemistry, Structural Biology, Cell Line, Tumor, Genetics, Ultraviolet light, Humans, Protein Interaction Domains and Motifs, Protein Interaction Maps, Phosphorylation, Molecular Biology, Vaccinia-related kinase 1, Protein Stability, Kinase, Intracellular Signaling Peptides and Proteins, Cell Biology, DNA-binding domain, Molecular biology, Cell biology, HEK293 Cells, Protein Multimerization, Tumor Suppressor Protein p53, Protein Processing, Post-Translational, Protein Binding
Abstract

DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA-contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1-p53 basal complex is an early-warning system for immediate cellular responses to DNA damage., I. L.-S. and A.V. have FPI and FPU fellowships respectively from Ministerio de Ciencia e Innovación. M.V.-C., M.S.-G. and A.C. have JAE-CSIC-Fondo Social Europeo fellowships. This work was supported by Grants from Ministerio de Educación, Ciencia e Innovación (SAF2010-14935 and CSD2007-0017) and Kutxa-Fundación Inbiomed to P.A.L.

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26. 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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