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1. A Machine Learning Strategy to Identity Exonic Splice Enhancers in Human Protein-coding Sequence

Author

Down, Thomas A., Leong, Bernard, and Hubbard, Tim J. P.

Subjects
Quantitative Biology - Genomics
Abstract

Background: Exonic splice enhancers are sequences embedded within exons which promote and regulate the splicing of the transcript in which they are located. A class of exonic splice enhancers are the SR proteins, which are thought to mediate interactions between splicing factors bound to the 5' and 3' splice sites. Method and results: We present a novel strategy for analysing protein-coding sequence by first randomizing the codons used at each position within the coding sequence, then applying a motif-based machine learning algorithm to compare the true and randomized sequences. This strategy identified a collection of motifs which can successfully discriminate between real and randomized coding sequence, including -- but not restricted to -- several previously reported splice enhancer elements. As well as successfully distinguishing coding exons from randomized sequences, we show that our model is able to recognize non-coding exons. Conclusions: Our strategy succeeded in detecting signals in coding exons which seem to be orthogonal to the sequences' primary function of coding for proteins. We believe that many of the motifs detected here may represent binding sites for previously unrecognized proteins which influence RNA splicing. We hope that this development will lead to improved knowledge of exonic splice enhancers, and new developments in the field of computational gene prediction., Comment: Submitted to Genome Research, 16 pages and 5 figures

Published
2004

2. Relevance Vector Machines for classifying points and regions in biological sequences

Author

Down, Thomas A. and Hubbard, Tim J. P.

Subjects
Quantitative Biology - Genomics
Abstract

The Relevance Vector Machine (RVM) is a recently developed machine learning framework capable of building simple models from large sets of candidate features. Here, we describe a protocol for using the RVM to explore very large numbers of candidate features, and a family of models which apply the power of the RVM to classifying and detecting interesting points and regions in biological sequence data. The models described here have been used successfully for predicting transcription start sites and other features in genome sequences., Comment: 16 pages, 3 figures

Published
2003

3. What can we learn from noncoding regions of similarity between genomes?

Author

Down, Thomas A. and Hubbard, Tim J. P.

Subjects
Quantitative Biology - Genomics
Abstract

Background: In addition to known protein-coding genes, large amount of apparently non-coding sequence are conserved between the human and mouse genomes. It seems reasonable to assume that these conserved regions are more likely to contain functional elements than less-conserved portions of the genome. Here we used a motif-oriented machine learning method to extract the strongest signal from a set of non-coding conserved sequences. Results: We successfully fitted models to reflect the non-coding sequences, and showed that the results were quite consistent for repeated training runs. Using the learned model to scan genomic sequence, we found that it often made predictions close to the start of annotated genes. We compared this method with other published promoter-prediction systems, and show that the set of promoters which are detected by this method seems to be substantially similar to that detected by existing methods. Conclusions: The results presented here indicate that the promoter signal is the strongest single motif-based signal in the non-coding functional fraction of the genome. They also lend support to the belief that there exists a substantial subset of promoter regions which share common features and are detectable by a variety of computational methods., Comment: 10 pages, 5 figures

Published
2003

5. The Distributed Annotation System for Integration of Biological Data

Author

Prlić, Andreas, Birney, Ewan, Cox, Tony, Down, Thomas A., Finn, Rob, Gräf, Stefan, Jackson, David, Kähäri, Andreas, Kulesha, Eugene, Pettett, Roger, Smith, James, Stalker, Jim, Hubbard, Tim J. P., Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Dough, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Istrail, Sorin, editor, Pevzner, Pavel, editor, Waterman, Michael, editor, Leser, Ulf, editor, Naumann, Felix, editor, and Eckman, Barbara, editor

Published
2006
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8. The UK10K project identifies rare variants in health and disease

Author

Walter, Klaudia, Min, Josine L., Huang, Jie, Crooks, Lucy, Memari, Yasin, Perry, John R. B., Xu, ChangJiang, Futema, Marta, Lawson, Daniel, Iotchkova, Valentina, Schiffels, Stephan, Hendricks, Audrey E., Danecek, Petr, Li, Rui, Floyd, James, Wain, Louise V., Humphries, Steve E., Barrett, Jeffrey C., Bala, Senduran, Clapham, Peter, Coates, Guy, Cox, Tony, Daly, Allan, Du, Yuanping, Edkins, Sarah, Ellis, Peter, Flicek, Paul, Guo, Xiaosen, Guo, Xueqin, Huang, Liren, Jackson, David K., Joyce, Chris, Keane, Thomas, Kolb-Kokocinski, Anja, Langford, Cordelia, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Maslen, John, McCarthy, Shane, (co-chair), Muddyman, Dawn, Quail, Michael A., Stalker, Jim, (co-chair), Sun, Jianping, Tian, Jing, Wang, Guangbiao, Wang, Jun, Wang, Yu, Wong, Kim, Zhang, Pingbo, Birney, Ewan, Boustred, Chris, Chen, Lu, Clement, Gail, Cocca, Massimiliano, Smith, George Davey, Day, Ian N. M., Day-Williams, Aaron, Down, Thomas, Dunham, Ian, Evans, David M., Gaunt, Tom R., Geihs, Matthias, Hart, Deborah, Howie, Bryan, Hubbard, Tim, Hysi, Pirro, Jamshidi, Yalda, Karczewski, Konrad J., Kemp, John P., Lachance, Genevieve, Lek, Monkol, Lopes, Margarida, MacArthur, Daniel G., Marchini, Jonathan, Mangino, Massimo, Mathieson, Iain, Metrustry, Sarah, Moayyeri, Alireza, Northstone, Kate, Panoutsopoulou, Kalliope, Paternoster, Lavinia, Quaye, Lydia, Richards, Brent J., (co-chair), Ring, Susan, Ritchie, Graham R. S., Shihab, Hashem A., Shin, So-Youn, Small, Kerrin S., Artigas, María Soler, Soranzo, Nicole, (co-chair), Southam, Lorraine, Spector, Timothy D., St Pourcain, Beate, Surdulescu, Gabriela, Tachmazidou, Ioanna, Timpson, Nicholas J., (co-chair), Tobin, Martin D., Valdes, Ana M., Visscher, Peter M., Ward, Kirsten, Wilson, Scott G., Yang, Jian, Zhang, Feng, Zheng, Hou-Feng, Anney, Richard, Ayub, Muhammad, Blackwood, Douglas, Bolton, Patrick F., Breen, Gerome, Collier, David A., Craddock, Nick, Curran, Sarah, Curtis, David, Gallagher, Louise, Geschwind, Daniel, Gurling, Hugh, Holmans, Peter, Lee, Irene, Lönnqvist, Jouko, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Morris, James, OʼDonovan, Michael C., Owen, Michael J., (co-chair), Palotie, Aarno, (co-chair), Parr, Jeremy R., Paunio, Tiina, Pietilainen, Olli, Rehnström, Karola, Sharp, Sally I., Skuse, David, St Clair, David, Suvisaari, Jaana, Walters, James T. R., Williams, Hywel J., Barroso, Inês, (co-chair), Bochukova, Elena, Bounds, Rebecca, Dominiczak, Anna, Farooqi, Sadaf I., (co-chair), Keogh, Julia, Marenne, Gaëlle, Morris, Andrew, OʼRahilly, Stephen, Porteous, David J., Smith, Blair H., Wheeler, Eleanor, Al Turki, Saeed, Anderson, Carl A., Antony, Dinu, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Fitzpatrick, David R., (co-chair), Foley, Reghan A., Franklin, Christopher S., Grozeva, Detelina, Hurles, Matthew E., (co-chair), Mitchison, Hannah M., Muntoni, Francesco, Onoufriadis, Alexandros, Parker, Victoria, Payne, Felicity, Raymond, Lucy F., Roberts, Nicola, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Spasic-Boskovic, Olivera, Stevens, Elizabeth, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Williamson, Kathleen A., Wilson, Crispian, Whyte, Tamieka, Ciampi, Antonio, Greenwood, Celia M. T., (co-chair), Oualkacha, Karim, Zeggini, Eleftheria, (co-chair), Bobrow, Martin, Griffin, Heather, Kaye, Jane, (co-chair), Kennedy, Karen, Kent, Alastair, Smee, Carol, Charlton, Ruth, Ekong, Rosemary, Khawaja, Farrah, Lopes, Luis R., Migone, Nicola, Payne, Stewart J., Plagnol, Vincent, (chair), Pollitt, Rebecca C., Povey, Sue, Ridout, Cheryl K., Robinson, Rachel L., Scott, Richard H., Shaw, Adam, Syrris, Petros, Taylor, Rohan, Vandersteen, Anthony M., Durbin, Richard, (chair), Amuzu, Antoinette, Casas, Juan Pablo, Chambers, John C., Dedoussis, George, Gambaro, Giovanni, Gasparini, Paolo, Isaacs, Aaron, Johnson, Jon, Kleber, Marcus E., Kooner, Jaspal S., Langenberg, Claudia, Luan, Jianʼan, Malerba, Giovanni, März, Winfried, Matchan, Angela, Morris, Richard, Nordestgaard, Børge G., Benn, Marianne, Scott, Robert A., Toniolo, Daniela, Traglia, Michela, Tybjaerg-Hansen, Anne, van Duijn, Cornelia M., van Leeuwen, Elisabeth M., Varbo, Anette, Whincup, Peter, Zaza, Gianluigi, and Zhang, Weihua

Published
2015
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11. Integrating biological data – the Distributed Annotation System

Author

Jones Philip, Jimenez Rafael C, Hubbard Tim JP, Hermjakob Henning, Finn Robert D, Down Thomas, Blankenburg Hagen, Birney Ewan, Albrecht Mario, Jenkinson Andrew M, Kähäri Andreas, Kulesha Eugene, Macías José R, Reeves Gabrielle A, and Prlić Andreas

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The Distributed Annotation System (DAS) is a widely adopted protocol for dynamically integrating a wide range of biological data from geographically diverse sources. DAS continues to expand its applicability and evolve in response to new challenges facing integrative bioinformatics. Results Here we describe the various infrastructure components of DAS and present a new extended version of the DAS specification. Version 1.53E incorporates several recent developments, including its extension to serve new data types and an ontology for protein features. Conclusion Our extensions to the DAS protocol have facilitated the integration of new data types, and our improvements to the existing DAS infrastructure have addressed recent challenges. The steadily increasing numbers of available data sources demonstrates further adoption of the DAS protocol.

Published
2008
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15. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Author

Yang, Yongjie, van der Klaauw, Agatha A., Zhu, Liangru, Cacciottolo, Tessa M., He, Yanlin, Stadler, Lukas K. J., Wang, Chunmei, Xu, Pingwen, Saito, Kenji, Hinton, Antentor, Yan, Xiaofeng, Keogh, Julia M., Henning, Elana, Banton, Matthew C., Hendricks, Audrey E., Bochukova, Elena G., Mistry, Vanisha, Lawler, Katherine L., Liao, Lan, Xu, Jianming, O'Rahilly, Stephen, Tong, Qingchun, Barroso, Ines, O'Malley, Bert W., Farooqi, I. Sadaf, Xu, Yong, Balasubramanian, Senduran, Clapham, Peter, Coates, Guy, Cox, Tony, Daly, Allan, Danecek, Petr, Du, Yuanping, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Flicek, Paul, Guo, Xiaosen, Guo, Xueqin, Huang, Liren, Jackson, David K., Joyce, Chris, Keane, Thomas, Kolb-Kokocinski, Anja, Langford, Cordelia, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Maslen, John, McCarthy, Shane, Muddyman, Dawn, Quail, Michael A., Stalker, Jim, Sun, Jianping, Tian, Jing, Wang, Guangbiao, Wang, Jun, Wang, Yu, Wong, Kim, Zhang, Pingbo, Birney, Ewan, Boustred, Chris, Brion, Marie-Jo, Chen, Lu, Clement, Gail, Smith, George Davey, Day, Ian N. M., Day-Williams, Aaron, Down, Thomas, Dunham, Ian, Evans, David M., Fatemifar, Ghazaleh, Gaunt, Tom R., Geihs, Matthias, Greenwood, Celia M. T., Hart, Deborah, Howie, Bryan, Huang, Jie, Hubbard, Tim, Hysi, Pirro, Iotchkova, Valentina, Jamshidi, Yalda, Kemp, John P., Lachance, Genevieve, Lawson, Daniel, Lek, Monkol, Lopes, Margarida, MacArthur, Daniel G., Marchini, Jonathan, Massimo, Mangino, Mathieson, Iain, Memari, Yasin, Metrustry, Sarah, Min, Josine L., Moayyeri, Alireza, Northstone, Kate, Panoutsopoulou, Kalliope, Paternoster, Lavinia, Perry, John R. B., Quaye, Lydia, Richards, J. Brent, Ring, Susan, Ritchie, Graham R. S., Schiffels, Stephan, Shihab, Hashem A., Shin, So-Youn, Small, Kerrin S., Artigas, Maria Soler, Soranzo, Nicole, Southam, Lorraine, Spector, Timothy D., St Pourcain, Beate, Surdulescu, Gabriela, Tachmazidou, Ioanna, Timpson, Nicholas J., Tobin, Martin D., Valdes, Ana M., Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Ward, Kirsten, Wilson, Scott G., Yang, Jian, Zeggini, Eleftheria, Zhang, Feng, Zheng, Hou-Feng, Anney, Richard, Ayub, Muhammad, Barrett, Jeffrey C., Blackwood, Douglas, Bolton, Patrick F., Breen, Gerome, Collier, David A., Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Gallagher, Louise, Geschwind, Daniel, Gurling, Hugh, Holmans, Peter, Lee, Irene, Lonnqvist, Jouko, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Morris, James, O'Donovan, Michael C., Owen, Michael J., Palotie, Aarno, Parr, Jeremy R., Paunio, Tiina, Pietilainen, Olli, Rehnstrom, Karola, Sharp, Sally I., Skuse, David, St Clair, David, Suvisaari, Jaana, Walters, James T. R., Williams, Hywel J., Bochukova, Elena, Bounds, Rebecca, Dominiczak, Anna, Keogh, Julia, Marenne, Gaelle, Morris, Andrew, Porteous, David J., Smith, Blair H., Wheeler, Eleanor, Al Turki, Saeed, Anderson, Carl A., Antony, Dinu, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Fitzpatrick, David R., Floyd, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Grozeva, Detelina, Humphries, Steve E., Hurles, Matthew E., Mitchison, Hannah M., Muntoni, Francesco, Onoufriadis, Alexandros, Parker, Victoria, Payne, Felicity, Plagnol, Vincent, Raymond, F. Lucy, Roberts, Nicola, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Spasic-Boskovic, Olivera, Stevens, Elizabeth, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Williamson, Kathleen A., Wilson, Crispian, Whyte, Tamieka, Ciampi, Antonio, Li, Rui, Oualkacha, Karim, Xu, ChangJiang, Bobrow, Martin, Griffin, Heather, Kaye, Jane, Kennedy, Karen, Kent, Alastair, Smee, Carol, Charlton, Ruth, Ekong, Rosemary, Khawaja, Farrah, Lopes, Luis R., Migone, Nicola, Payne, Stewart J., Pollitt, Rebecca C., Povey, Sue, Ridout, Cheryl K., Robinson, Rachel L., Scott, Richard H., Shaw, Adam, Syrris, Petros, Taylor, Rohan, Vandersteen, Anthony M., Amuzu, Antoinette, Casas, Juan Pablo, Chambers, John C., Cocca, Massimiliano, Dedoussis, George, Gambaro, Giovanni, Gasparini, Paolo, Isaacs, Aaron, Johnson, Jon, Kleber, Marcus E., Kooner, Jaspal S., Langenberg, Claudia, Luan, Jian'an, Malerba, Giovanni, Marz, Winfried, Matchan, Angela, Morris, Richard, Nordestgaard, Børge G., Benn, Marianne, Scott, Robert A., Toniolo, Daniela, Traglia, Michela, Tybjaerg-Hansen, Anne, van Duijn, Cornelia M., van Leeuwen, Elisabeth M., Varbo, Anette, Whincup, Peter, Zaza, Gianluigi, and Zhang, Weihua

Published
2019
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19. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Author

Haworth, Simon, Shapland, Chin Yang, Hayward, Caroline, Prins, Bram P., Felix, Janine F., Medina-Gomez, Carolina, Rivadeneira, Fernando, Wang, Carol, Ahluwalia, Tarunveer S., Vrijheid, Martine, Guxens, Monica, Sunyer, Jordi, Tachmazidou, Ioanna, Walter, Klaudia, Iotchkova, Valentina, Jackson, Andrew, Cleal, Louise, Huffmann, Jennifer, Min, Josine L., Sass, Laerke, Timmers, Paul R. H. J., Al Turki, Saeed, Anderson, Carl A., Anney, Richard, Antony, Dinu, Artigas, Maria Soler, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Barroso, Ines, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick F., Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Cocca, Massimiliano, Collier, David A., Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N. M., Day-Williams, Aaron, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evans, David M., Farooqi, I. Sadaf, Fitzpatrick, David R., Flicek, Paul, Floyd, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel, Greenwood, Celia M. T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey E., Holmans, Peter, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Keogh, Julia, Khawaja, Farrah, van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lonnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Marenne, Gaelle, Maslen, John, Mathieson, Iain, McCarthy, Shane, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Mitchison, Hannah M., Moayyeri, Alireza, Morris, Andrew, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., O'Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnstrom, Karola, Richards, J. Brent, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So-Youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, Blair H., Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D., St Clair, David, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Tobin, Martin D., Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Eleanor, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, ChangJiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou-Feng, Smith, George Davey, Fisher, Simon E., Wilson, James F., Cole, Tim J., Fernandez-Orth, Dietmar, Bonnelykke, Klaus, Bisgaard, Hans, Pennell, Craig E., Jaddoe, Vincent W. V., Dedoussis, George, Timpson, Nicholas, Zeggini, Eleftheria, Vitart, Veronique, St Pourcain, Beate, Haworth, Simon, Shapland, Chin Yang, Hayward, Caroline, Prins, Bram P., Felix, Janine F., Medina-Gomez, Carolina, Rivadeneira, Fernando, Wang, Carol, Ahluwalia, Tarunveer S., Vrijheid, Martine, Guxens, Monica, Sunyer, Jordi, Tachmazidou, Ioanna, Walter, Klaudia, Iotchkova, Valentina, Jackson, Andrew, Cleal, Louise, Huffmann, Jennifer, Min, Josine L., Sass, Laerke, Timmers, Paul R. H. J., Al Turki, Saeed, Anderson, Carl A., Anney, Richard, Antony, Dinu, Artigas, Maria Soler, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Barroso, Ines, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick F., Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Cocca, Massimiliano, Collier, David A., Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N. M., Day-Williams, Aaron, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evans, David M., Farooqi, I. Sadaf, Fitzpatrick, David R., Flicek, Paul, Floyd, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel, Greenwood, Celia M. T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey E., Holmans, Peter, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Keogh, Julia, Khawaja, Farrah, van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lonnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Marenne, Gaelle, Maslen, John, Mathieson, Iain, McCarthy, Shane, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Mitchison, Hannah M., Moayyeri, Alireza, Morris, Andrew, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., O'Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnstrom, Karola, Richards, J. Brent, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So-Youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, Blair H., Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D., St Clair, David, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Tobin, Martin D., Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Eleanor, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, ChangJiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou-Feng, Smith, George Davey, Fisher, Simon E., Wilson, James F., Cole, Tim J., Fernandez-Orth, Dietmar, Bonnelykke, Klaus, Bisgaard, Hans, Pennell, Craig E., Jaddoe, Vincent W. V., Dedoussis, George, Timpson, Nicholas, Zeggini, Eleftheria, Vitart, Veronique, and St Pourcain, Beate

Abstract

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Published
2019

21. An interactive genome browser of association results from the UK10K cohorts project

Author

Geihs, Matthias, Yan, Ying, Walter, Klaudia, Huang, Jie, Memari, Yasin, Min, Josine L, Mead, Daniel, UK10K Consortium, Hubbard, Tim J, Timpson, Nicholas J, Down, Thomas A, Soranzo, Nicole, Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository

Subjects
Genome, Human, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, natural sciences, Genetic Association Studies, Linkage Disequilibrium, Software
Abstract

UNLABELLED: High-throughput sequencing technologies survey genetic variation at genome scale and are increasingly used to study the contribution of rare and low-frequency genetic variants to human traits. As part of the Cohorts arm of the UK10K project, genetic variants called from low-read depth (average 7×) whole genome sequencing of 3621 cohort individuals were analysed for statistical associations with 64 different phenotypic traits of biomedical importance. Here, we describe a novel genome browser based on the Biodalliance platform developed to provide interactive access to the association results of the project. AVAILABILITY AND IMPLEMENTATION: The browser is available at http://www.uk10k.org/dalliance.html. Source code for the Biodalliance platform is available under a BSD license from http://github.com/dasmoth/dalliance, and for the LD-display plugin and backend from http://github.com/dasmoth/ldserv.

Published
2018
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22. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Gorman, Kathleen M., primary, Meyer, Esther, additional, Grozeva, Detelina, additional, Spinelli, Egidio, additional, McTague, Amy, additional, Sanchis-Juan, Alba, additional, Carss, Keren J., additional, Bryant, Emily, additional, Reich, Adi, additional, Schneider, Amy L., additional, Pressler, Ronit M., additional, Simpson, Michael A., additional, Debelle, Geoff D., additional, Wassmer, Evangeline, additional, Morton, Jenny, additional, Sieciechowicz, Diana, additional, Jan-Kamsteeg, Eric, additional, Paciorkowski, Alex R., additional, King, Mary D., additional, Cross, J. Helen, additional, Poduri, Annapurna, additional, Mefford, Heather C., additional, Scheffer, Ingrid E., additional, Haack, Tobias B., additional, McCullagh, Gary, additional, Millichap, John J., additional, Carvill, Gemma L., additional, Clayton-Smith, Jill, additional, Maher, Eamonn R., additional, Raymond, F. Lucy, additional, Kurian, Manju A., additional, McRae, Jeremy F., additional, Clayton, Stephen, additional, Fitzgerald, Tomas W., additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, Alejandro, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M., additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D., additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E., additional, Singh, Tarjinder, additional, Tivey, Adrian R., additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Banka, Siddharth, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A. Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J., additional, Burn, John, additional, Canham, Natalie, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N., additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cox, Helen, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D’Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, Andrew, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Gill, Harinder, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Rachel, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, Dhavendra, additional, Kumar, V. K. Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A., additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McKee, Shane, additional, McMullan, Dominic J., additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O’Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Parker, Michael J., additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T., additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Rankin, Julia, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Temple, I. Karen, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Vogt, Julie, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellåker, Chris, additional, Parker, Michael, additional, Firth, Helen V., additional, Wright, Caroline F., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, Hurles, Matthew E., additional, Al Turki, Saeed, additional, Anderson, Carl, additional, Anney, Richard, additional, Antony, Dinu, additional, Artigas, Maria Soler, additional, Ayub, Muhammad, additional, Balasubramaniam, Senduran, additional, Barroso, Inês, additional, Beales, Phil, additional, Bentham, Jamie, additional, Bhattacharya, Shoumo, additional, Birney, Ewan, additional, Blackwood, Douglas, additional, Bobrow, Martin, additional, Bochukova, Elena, additional, Bolton, Patrick, additional, Bounds, Rebecca, additional, Boustred, Chris, additional, Breen, Gerome, additional, Calissano, Mattia, additional, Carss, Keren, additional, Chatterjee, Krishna, additional, Chen, Lu, additional, Ciampi, Antonio, additional, Cirak, Sebhattin, additional, Clapham, Peter, additional, Clement, Gail, additional, Coates, Guy, additional, Collier, David, additional, Cosgrove, Catherine, additional, Cox, Tony, additional, Craddock, Nick, additional, Crooks, Lucy, additional, Curran, Sarah, additional, Curtis, David, additional, Daly, Allan, additional, Day-Williams, Aaron, additional, Day, Ian N.M., additional, Down, Thomas, additional, Du, Yuanping, additional, Dunham, Ian, additional, Edkins, Sarah, additional, Ellis, Peter, additional, Evans, David, additional, Faroogi, Sadaf, additional, Fatemifar, Ghazaleh, additional, Fitzpatrick, David R., additional, Flicek, Paul, additional, Flyod, James, additional, Foley, A. Reghan, additional, Franklin, Christopher S., additional, Futema, Marta, additional, Gallagher, Louise, additional, Geihs, Matthias, additional, Geschwind, Daniel, additional, Griffin, Heather, additional, Guo, Xueqin, additional, Guo, Xiaosen, additional, Gurling, Hugh, additional, Hart, Deborah, additional, Hendricks, Audrey, additional, Holmans, Peter, additional, Howie, Bryan, additional, Huang, Liren, additional, Hubbard, Tim, additional, Humphries, Steve E., additional, Hysi, Pirro, additional, Jackson, David K., additional, Jamshidi, Yalda, additional, Jing, Tian, additional, Joyce, Chris, additional, Kaye, Jane, additional, Keane, Thomas, additional, Keogh, Julia, additional, Kemp, John, additional, Kennedy, Karen, additional, Kolb-Kokocinski, Anja, additional, Lachance, Genevieve, additional, Langford, Cordelia, additional, Lawson, Daniel, additional, Lee, Irene, additional, Lek, Monkol, additional, Liang, Jieqin, additional, Lin, Hong, additional, Li, Rui, additional, Li, Yingrui, additional, Liu, Ryan, additional, Lönnqvist, Jouko, additional, Lopes, Margarida, additional, Iotchkova, Valentina, additional, MacArthur, Daniel, additional, Marchini, Jonathan, additional, Maslen, John, additional, Massimo, Mangino, additional, Mathieson, Iain, additional, Marenne, Gaëlle, additional, McGuffin, Peter, additional, McIntosh, Andrew, additional, McKechanie, Andrew G., additional, McQuillin, Andrew, additional, Metrustry, Sarah, additional, Mitchison, Hannah, additional, Moayyeri, Alireza, additional, Morris, James, additional, Muntoni, Francesco, additional, Northstone, Kate, additional, O'Donnovan, Michael, additional, Onoufriadis, Alexandros, additional, O'Rahilly, Stephen, additional, Oualkacha, Karim, additional, Owen, Michael J., additional, Palotie, Aarno, additional, Panoutsopoulou, Kalliope, additional, Parker, Victoria, additional, Parr, Jeremy R., additional, Paternoster, Lavinia, additional, Paunio, Tiina, additional, Payne, Felicity, additional, Pietilainen, Olli, additional, Plagnol, Vincent, additional, Quaye, Lydia, additional, Quail, Michael A., additional, Rehnström, Karola, additional, Ring, Susan, additional, Ritchie, Graham R.S., additional, Roberts, Nicola, additional, Savage, David B., additional, Scambler, Peter, additional, Schiffels, Stephen, additional, Schmidts, Miriam, additional, Schoenmakers, Nadia, additional, Semple, Robert K., additional, Serra, Eva, additional, Sharp, Sally I., additional, Shin, So-Youn, additional, Skuse, David, additional, Small, Kerrin, additional, Southam, Lorraine, additional, Spasic-Boskovic, Olivera, additional, St Clair, David, additional, Stalker, Jim, additional, Stevens, Elizabeth, additional, St Pourcian, Beate, additional, Sun, Jianping, additional, Suvisaari, Jaana, additional, Tachmazidou, Ionna, additional, Tobin, Martin D., additional, Valdes, Ana, additional, Van Kogelenberg, Margriet, additional, Visscher, Peter M., additional, Wain, Louise V., additional, Walters, James T.R., additional, Wang, Guangbiao, additional, Wang, Jun, additional, Wang, Yu, additional, Ward, Kirsten, additional, Wheeler, Elanor, additional, Whyte, Tamieka, additional, Williams, Hywel, additional, Williamson, Kathleen A., additional, Wilson, Crispian, additional, Wong, Kim, additional, Xu, ChangJiang, additional, Yang, Jian, additional, Zhang, Fend, additional, Zhang, Pingbo, additional, Aitman, Timothy, additional, Alachkar, Hana, additional, Ali, Sonia, additional, Allen, Louise, additional, Allsup, David, additional, Ambegaonkar, Gautum, additional, Anderson, Julie, additional, Antrobus, Richard, additional, Arno, Gavin, additional, Arumugakani, Gururaj, additional, Ashford, Sofie, additional, Astle, William, additional, Attwood, Antony, additional, Austin, Steve, additional, Bacchelli, Chiara, additional, Bakchoul, Tamam, additional, Bariana, Tadbir K., additional, Baxendale, Helen, additional, Bennett, David, additional, Bethune, Claire, additional, Bibi, Shahnaz, additional, Bleda, Marta, additional, Boggard, Harm, additional, Bolton-Maggs, Paula, additional, Booth, Claire, additional, Bradley, John R., additional, Brady, Angie, additional, Brown, Matthew, additional, Browning, Michael, additional, Bryson, Christine, additional, Burns, Siobhan, additional, Calleja, Paul, additional, Carmichael, Jenny, additional, Caulfield, Mark, additional, Chalmers, Elizabeth, additional, Chandra, Anita, additional, Chinnery, Patrick, additional, Chitre, Manali, additional, Church, Colin, additional, Clement, Emma, additional, Clements-Brod, Naomi, additional, Coghlan, Gerry, additional, Collins, Peter, additional, Cooper, Nichola, additional, Creaser-Myers, Amanda, additional, DaCosta, Rosa, additional, Daugherty, Louise, additional, Davies, Sophie, additional, Davis, John, additional, De Vries, Minka, additional, Deegan, Patrick, additional, Deevi, Sri V.V., additional, Devlin, Lisa, additional, Dewhurst, Eleanor, additional, Doffinger, Rainer, additional, Dormand, Natalie, additional, Drewe, Elizabeth, additional, Edgar, David, additional, Egner, William, additional, Erber, Wendy N., additional, Erwood, Marie, additional, Everington, Tamara, additional, Favier, Remi, additional, Firth, Helen, additional, Fletcher, Debra, additional, Fox, James C., additional, Frary, Amy, additional, Freson, Kathleen, additional, Furie, Bruce, additional, Furnell, Abigail, additional, Gale, Daniel, additional, Gardham, Alice, additional, Gattens, Michael, additional, Ghataorhe, Pavandeep K., additional, Ghurye, Rohit, additional, Gibbs, Simon, additional, Gilmour, Kimberley, additional, Gissen, Paul, additional, Goddard, Sarah, additional, Gomez, Keith, additional, Gordins, Pavel, additional, Gräf, Stefan, additional, Greene, Daniel, additional, Greenhalgh, Alan, additional, Greinacher, Andreas, additional, Grigoriadou, Sofia, additional, Hackett, Scott, additional, Hadinnapola, Charaka, additional, Hague, Rosie, additional, Haimel, Matthias, additional, Halmagyi, Csaba, additional, Hammerton, Tracey, additional, Hart, Daniel, additional, Hayman, Grant, additional, Heemskerk, Johan W.M., additional, Henderson, Robert, additional, Hensiek, Anke, additional, Henskens, Yvonne, additional, Herwadkar, Archana, additional, Hu, Fengyuan, additional, Huissoon, Aarnoud, additional, Humbert, Marc, additional, James, Roger, additional, Jolles, Stephen, additional, Kazmi, Rashid, additional, Keeling, David, additional, Kelleher, Peter, additional, Kelly, Anne M., additional, Kennedy, Fiona, additional, Kiely, David, additional, Kingston, Nathalie, additional, Koziell, Ania, additional, Krishnakumar, Deepa, additional, Kuijpers, Taco W., additional, Kumararatne, Dinakantha, additional, Kurian, Manju, additional, Laffan, Michael A., additional, Lambert, Michele P., additional, Allen, Hana Lango, additional, Lawrie, Allan, additional, Lear, Sara, additional, Lentaigne, Claire, additional, Liesner, Ri, additional, Linger, Rachel, additional, Longhurst, Hilary, additional, Lorenzo, Lorena, additional, Machado, Rajiv, additional, Mackenzie, Rob, additional, MacLaren, Robert, additional, Maher, Eamonn, additional, Maimaris, Jesmeen, additional, Mangles, Sarah, additional, Manson, Ania, additional, Mapeta, Rutendo, additional, Markus, Hugh S., additional, Martin, Jennifer, additional, Masati, Larahmie, additional, Mathias, Mary, additional, Matser, Vera, additional, Maw, Anna, additional, McDermott, Elizabeth, additional, McJannet, Coleen, additional, Meacham, Stuart, additional, Meehan, Sharon, additional, Megy, Karyn, additional, Michaelides, Michel, additional, Millar, Carolyn M., additional, Moledina, Shahin, additional, Moore, Anthony, additional, Morrell, Nicholas, additional, Mumford, Andrew, additional, Murng, Sai, additional, Murphy, Elaine, additional, Nejentsev, Sergey, additional, Noorani, Sadia, additional, Nurden, Paquita, additional, Oksenhendler, Eric, additional, Ouwehand, Willem H., additional, Papadia, Sofia, additional, Parker, Alasdair, additional, Pasi, John, additional, Patch, Chris, additional, Payne, Jeanette, additional, Peacock, Andrew, additional, Peerlinck, Kathelijne, additional, Penkett, Christopher J., additional, Pepke-Zaba, Joanna, additional, Perry, David J., additional, Pollock, Val, additional, Polwarth, Gary, additional, Ponsford, Mark, additional, Qasim, Waseem, additional, Quinti, Isabella, additional, Rankin, Stuart, additional, Rehnstrom, Karola, additional, Reid, Evan, additional, Rhodes, Christopher J., additional, Richards, Michael, additional, Richardson, Sylvia, additional, Richter, Alex, additional, Roberts, Irene, additional, Rondina, Matthew, additional, Roughley, Catherine, additional, Rue-Albrecht, Kevin, additional, Samarghitean, Crina, additional, Santra, Saikat, additional, Sargur, Ravishankar, additional, Savic, Sinisa, additional, Schulman, Sol, additional, Schulze, Harald, additional, Scully, Marie, additional, Seneviratne, Suranjith, additional, Sewell, Carrock, additional, Shamardina, Olga, additional, Shipley, Debbie, additional, Simeoni, Ilenia, additional, Sivapalaratnam, Suthesh, additional, Smith, Kenneth, additional, Sohal, Aman, additional, Southgate, Laura, additional, Staines, Simon, additional, Staples, Emily, additional, Stauss, Hans, additional, Stein, Penelope, additional, Stephens, Jonathan, additional, Stirrups, Kathleen, additional, Stock, Sophie, additional, Suntharalingam, Jay, additional, Tait, R. Campbell, additional, Talks, Kate, additional, Tan, Yvonne, additional, Thachil, Jecko, additional, Thaventhiran, James, additional, Thomas, Ellen, additional, Thomas, Moira, additional, Thompson, Dorothy, additional, Thrasher, Adrian, additional, Titterton, Catherine, additional, Toh, Cheng-Hock, additional, Toshner, Mark, additional, Treacy, Carmen, additional, Trembath, Richard, additional, Tuna, Salih, additional, Turek, Wojciech, additional, Turro, Ernest, additional, Van Geet, Chris, additional, Veltman, Marijke, additional, von Ziegenweldt, Julie, additional, Vonk Noordegraaf, Anton, additional, Wanjiku, Ivy, additional, Warner, Timothy Q., additional, Watkins, Hugh, additional, Webster, Andrew, additional, Welch, Steve, additional, Westbury, Sarah, additional, Wharton, John, additional, Whitehorn, Deborah, additional, Wilkins, Martin, additional, Willcocks, Lisa, additional, Williamson, Catherine, additional, Woods, Geoffrey, additional, Wort, John, additional, Yeatman, Nigel, additional, Yong, Patrick, additional, Young, Tim, additional, and Yu, Ping, additional

Published
2019
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23. Genome-wide conserved consensus transcription factor binding motifs are hyper-methylated

Author

Down Thomas A, Bennett Martin R, Goh Hock-Guan, Movassagh Mehregan, Choy Mun-Kit, and Foo Roger SY

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background DNA methylation can regulate gene expression by modulating the interaction between DNA and proteins or protein complexes. Conserved consensus motifs exist across the human genome ("predicted transcription factor binding sites": "predicted TFBS") but the large majority of these are proven by chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) not to be biological transcription factor binding sites ("empirical TFBS"). We hypothesize that DNA methylation at conserved consensus motifs prevents promiscuous or disorderly transcription factor binding. Results Using genome-wide methylation maps of the human heart and sperm, we found that all conserved consensus motifs as well as the subset of those that reside outside CpG islands have an aggregate profile of hyper-methylation. In contrast, empirical TFBS with conserved consensus motifs have a profile of hypo-methylation. 40% of empirical TFBS with conserved consensus motifs resided in CpG islands whereas only 7% of all conserved consensus motifs were in CpG islands. Finally we further identified a minority subset of TF whose profiles are either hypo-methylated or neutral at their respective conserved consensus motifs implicating that these TF may be responsible for establishing or maintaining an un-methylated DNA state, or whose binding is not regulated by DNA methylation. Conclusions Our analysis supports the hypothesis that at least for a subset of TF, empirical binding to conserved consensus motifs genome-wide may be controlled by DNA methylation.

Published
2010
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24. Metamotifs - a generative model for building families of nucleotide position weight matrices

Author

Down Thomas A, Piipari Matias, and Hubbard Tim JP

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Development of high-throughput methods for measuring DNA interactions of transcription factors together with computational advances in short motif inference algorithms is expanding our understanding of transcription factor binding site motifs. The consequential growth of sequence motif data sets makes it important to systematically group and categorise regulatory motifs. It has been shown that there are familial tendencies in DNA sequence motifs that are predictive of the family of factors that binds them. Further development of methods that detect and describe familial motif trends has the potential to help in measuring the similarity of novel computational motif predictions to previously known data and sensitively detecting regulatory motifs similar to previously known ones from novel sequence. Results We propose a probabilistic model for position weight matrix (PWM) sequence motif families. The model, which we call the 'metamotif' describes recurring familial patterns in a set of motifs. The metamotif framework models variation within a family of sequence motifs. It allows for simultaneous estimation of a series of independent metamotifs from input position weight matrix (PWM) motif data and does not assume that all input motif columns contribute to a familial pattern. We describe an algorithm for inferring metamotifs from weight matrix data. We then demonstrate the use of the model in two practical tasks: in the Bayesian NestedMICA model inference algorithm as a PWM prior to enhance motif inference sensitivity, and in a motif classification task where motifs are labelled according to their interacting DNA binding domain. Conclusions We show that metamotifs can be used as PWM priors in the NestedMICA motif inference algorithm to dramatically increase the sensitivity to infer motifs. Metamotifs were also successfully applied to a motif classification problem where sequence motif features were used to predict the family of protein DNA binding domains that would interact with it. The metamotif based classifier is shown to compare favourably to previous related methods. The metamotif has great potential for further use in machine learning tasks related to especially de novo computational sequence motif inference. The metamotif methods presented have been incorporated into the NestedMICA suite.

Published
2010
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25. NestedMICA as an ab initio protein motif discovery tool

Author

Down Thomas A, Doğruel Mutlu, and Hubbard Tim JP

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Discovering overrepresented patterns in amino acid sequences is an important step in protein functional element identification. We adapted and extended NestedMICA, an ab initio motif finder originally developed for finding transcription binding site motifs, to find short protein signals, and compared its performance with another popular protein motif finder, MEME. NestedMICA, an open source protein motif discovery tool written in Java, is driven by a Monte Carlo technique called Nested Sampling. It uses multi-class sequence background models to represent different "uninteresting" parts of sequences that do not contain motifs of interest. In order to assess NestedMICA as a protein motif finder, we have tested it on synthetic datasets produced by spiking instances of known motifs into a randomly selected set of protein sequences. NestedMICA was also tested using a biologically-authentic test set, where we evaluated its performance with respect to varying sequence length. Results Generally NestedMICA recovered most of the short (3–9 amino acid long) test protein motifs spiked into a test set of sequences at different frequencies. We showed that it can be used to find multiple motifs at the same time, too. In all the assessment experiments we carried out, its overall motif discovery performance was better than that of MEME. Conclusion NestedMICA proved itself to be a robust and sensitive ab initio protein motif finder, even for relatively short motifs that exist in only a small fraction of sequences. Availability NestedMICA is available under the Lesser GPL open-source license from: http://www.sanger.ac.uk/Software/analysis/nmica/

Published
2008
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26. Integrating sequence and structural biology with DAS

Author

Finn Robert D, Kulesha Eugene, Down Thomas A, Prlić Andreas, Kähäri Andreas, and Hubbard Tim JP

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The Distributed Annotation System (DAS) is a network protocol for exchanging biological data. It is frequently used to share annotations of genomes and protein sequence. Results Here we present several extensions to the current DAS 1.5 protocol. These provide new commands to share alignments, three dimensional molecular structure data, add the possibility for registration and discovery of DAS servers, and provide a convention how to provide different types of data plots. We present examples of web sites and applications that use the new extensions. We operate a public registry of DAS sources, which now includes entries for more than 250 distinct sources. Conclusion Our DAS extensions are essential for the management of the growing number of services and exchange of diverse biological data sets. In addition the extensions allow new types of applications to be developed and scientific questions to be addressed. The registry of DAS sources is available at http://www.dasregistry.org

Published
2007
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27. A machine learning strategy to identify candidate binding sites in human protein-coding sequence

Author

Leong Bernard, Down Thomas, and Hubbard Tim JP

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background The splicing of RNA transcripts is thought to be partly promoted and regulated by sequences embedded within exons. Known sequences include binding sites for SR proteins, which are thought to mediate interactions between splicing factors bound to the 5' and 3' splice sites. It would be useful to identify further candidate sequences, however identifying them computationally is hard since exon sequences are also constrained by their functional role in coding for proteins. Results This strategy identified a collection of motifs including several previously reported splice enhancer elements. Although only trained on coding exons, the model discriminates both coding and non-coding exons from intragenic sequence. Conclusion We have trained a computational model able to detect signals in coding exons which seem to be orthogonal to the sequences' primary function of coding for proteins. We believe that many of the motifs detected here represent binding sites for both previously unrecognized proteins which influence RNA splicing as well as other regulatory elements.

Published
2006
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28. What can we learn from noncoding regions of similarity between genomes?

Author

Hubbard Tim JP and Down Thomas A

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background In addition to known protein-coding genes, large amounts of apparently non-coding sequence are conserved between the human and mouse genomes. It seems reasonable to assume that these conserved regions are more likely to contain functional elements than less-conserved portions of the genome. Methods Here we used a motif-oriented machine learning method based on the Relevance Vector Machine algorithm to extract the strongest signal from a set of non-coding conserved sequences. Results We successfully fitted models to reflect the non-coding sequences, and showed that the results were quite consistent for repeated training runs. Using the learned models to scan genomic sequence, we found that they often made predictions close to the start of annotated genes. We compared this method with other published promoter-prediction systems, and showed that the set of promoters which are detected by this method is substantially similar to that detected by existing methods. Conclusions The results presented here indicate that the promoter signal is the strongest single motif-based signal in the non-coding functional fraction of the genome. They also lend support to the belief that there exists a substantial subset of promoter regions which share several common features including, but not restricted to, a relative abundance of CpG dinucleotides. This subset is detectable by a variety of distinct computational methods.

Published
2004
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29. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaëlle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Körner, Antje, Muddyman, Dawn, McCarthy, Shane, Hinney, Anke, Hebebrand, Johannes, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M M, Butterworth, Adam S., Danesh, John, Nordestgaard, Børge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inês, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nicholas, Jäckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, Anderson, Carl A, Anney, Richard, Antony, Dinu, Soler Artigas, María, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C, Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Douglas, Bobrow, Martin, Bolton, Patrick F., Boustred, Chris, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A, Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N M, Day-Williams, Aaron G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., Holmans, Peter A, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro G., Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M, Moayyeri, Alireza, Morris, Andrew D., Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnström, Karola, Richards, J Brent, Ridout, Cheryl K., Ring, Susan M., Ritchie, Graham R.S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So Youn, Skuse, David, Small, Kerrin S, Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D, St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela L, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D, Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou Feng, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaã«lle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Kã¶rner, Antje, Muddyman, Dawn, Mccarthy, Shane, Hinney, Anke, Hebebrand, Johanne, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M., Butterworth, Adam S., Danesh, John, Nordestgaard, Bã¸rge G, Nielsen, Sune F, Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inãª, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nichola, Jã¤ckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjã¸nneland, Anne, Clavel chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sã¡nchez, Marã­a josã©, Navarro, Carmen, Moreno iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Turki, Saeed Al, Anderson, Carl A., Anney, Richard, Antony, Dinu, Soler Artigas, Marã­a, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Dougla, Bobrow, Martin, Bolton, Patrick F., Boustred, Chri, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A., Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N. M., Day williams, Aaron, Dominiczak, Anna, Down, Thoma, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., Fitzpatrick, David R., Flicek, Paul, Floyd, Jame, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthia, Geschwind, Daniel, Greenwood, Celia M. T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Holmans, Peter, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chri, Karczewski, Konrad J., Kaye, Jane, Keane, Thoma, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lã¶nnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, Macarthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, Mcguffin, Peter, Mcintosh, Andrew M., Mckechanie, Andrew G., Mcquillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M., Moayyeri, Alireza, Morris, Andrew, Morris, Jame, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandro, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnstrã¶m, Karola, Richards, J. Brent, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic boskovic, Olivera, Spector, Timothy D., St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petro, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D., Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, and Zheng, Hou feng

Subjects
Multidisciplinary, Journal Article, General
Abstract

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as describedw previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF∼0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Published
2017

30. Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Author

UMC Utrecht, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaëlle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Körner, Antje, Muddyman, Dawn, McCarthy, Shane, Hinney, Anke, Hebebrand, Johannes, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M M, Butterworth, Adam S., Danesh, John, Nordestgaard, Børge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inês, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nicholas, Jäckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, Anderson, Carl A, Anney, Richard, Antony, Dinu, Soler Artigas, María, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C, Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Douglas, Bobrow, Martin, Bolton, Patrick F., Boustred, Chris, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A, Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N M, Day-Williams, Aaron G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., Holmans, Peter A, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro G., Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M, Moayyeri, Alireza, Morris, Andrew D., Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnström, Karola, Richards, J Brent, Ridout, Cheryl K., Ring, Susan M., Ritchie, Graham R.S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So Youn, Skuse, David, Small, Kerrin S, Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D, St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela L, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D, Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, Zheng, Hou Feng, UMC Utrecht, Cardiovasculaire Epidemiologie, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Hendricks, Audrey E., Bochukova, Elena G., Marenne, Gaëlle, Keogh, Julia M., Atanassova, Neli, Bounds, Rebecca, Wheeler, Eleanor, Mistry, Vanisha, Henning, Elana, Körner, Antje, Muddyman, Dawn, McCarthy, Shane, Hinney, Anke, Hebebrand, Johannes, Scott, Robert A., Langenberg, Claudia, Wareham, Nick J., Surendran, Praveen, Howson, Joanna M M, Butterworth, Adam S., Danesh, John, Nordestgaard, Børge G., Nielsen, Sune F., Afzal, Shoaib, Papadia, Sofia, Ashford, Sofie, Garg, Sumedha, Millhauser, Glenn L., Palomino, Rafael I., Kwasniewska, Alexandra, Tachmazidou, Ioanna, O'Rahilly, Stephen, Zeggini, Eleftheria, Barroso, Inês, Farooqi, I. Sadaf, Benzeval, Michaela, Burton, Jonathan, Buck, Nicholas, Jäckle, Annette, Kumari, Meena, Laurie, Heather, Lynn, Peter, Pudney, Stephen, Rabe, Birgitta, Wolke, Dieter, Overvad, Kim, Tjønneland, Anne, Clavel-Chapelon, Francoise, Kaaks, Rudolf, Boeing, Heiner, Trichopoulou, Antonia, Ferrari, Pietro, Palli, Domenico, Krogha, Vittorio, Panico, Salvatore, Tuminoa, Rosario, Matullo, Giuseppe, Boer, Jolanda Ma, Van Der Schouw, Yvonne, Weiderpass, Elisabete, Quiros, J. Ramon, Sánchez, María José, Navarro, Carmen, Moreno-Iribas, Conchi, Arriola, Larraitz, Melander, Olle, Wennberg, Patrik, Key, Timothy J., Riboli, Elio, Al-Turki, Saeed, Anderson, Carl A, Anney, Richard, Antony, Dinu, Soler Artigas, María, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C, Beales, Phil, Bentham, Jamie, Bhattacharyaa, Shoumo, Birney, Ewan, Blackwooda, Douglas, Bobrow, Martin, Bolton, Patrick F., Boustred, Chris, Breen, Gerome, Calissanoa, Mattia, Carss, Keren, Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampia, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Coccaa, Massimiliano, Collier, David A, Cosgrove, Catherine, Coxa, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Danecek, Petr, Day, Ian N M, Day-Williams, Aaron G, Dominiczak, Anna, Down, Thomas, Du, Yuanping, Dunham, Ian, Durbin, Richard, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evansa, David M., FitzPatrick, David R., Flicek, Paul, Floyd, James S., Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel H., Greenwood, Celia M.T., Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah J., Holmans, Peter A, Howie, Bryan, Huang, Jie, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro G., Iotchkova, Valentina, Jackson, David K., Jamshidi, Yalda, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Khawaja, Farrah, Van Kogelenberg, Margriet, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, MacArthur, Daniel G., Mangino, Massimo, Marchini, Jonathan, Maslen, John, Mathieson, Iain, McGuffin, Peter, McIntosh, Andrew M., McKechanie, Andrew G., McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Migone, Nicola, Min, Josine L., Mitchison, Hannah M, Moayyeri, Alireza, Morris, Andrew D., Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donovan, Michael C., Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Porteous, David J., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, F. Lucy, Rehnström, Karola, Richards, J Brent, Ridout, Cheryl K., Ring, Susan M., Ritchie, Graham R.S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So Youn, Skuse, David, Small, Kerrin S, Smee, Carol, Smith, Blair H., Davey Smith, George, Soranzo, Nicole, Southam, Lorraine, Spasic-Boskovic, Olivera, Spector, Timothy D, St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela L, Suvisaari, Jaana, Syrris, Petros, Taylor, Rohan, Tian, Jing, Timpson, Nicholas J., Tobin, Martin D, Valdes, Ana M., Vandersteen, Anthony M., Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walter, Klaudia, Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Nai-Yu, Ward, Kirsten, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zhang, Feng, Zhang, Pingbo, and Zheng, Hou Feng

Published
2017

31. Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains

Author

Rakyan, Vardhman K., Down, Thomas A., Maslau, Siarhei, Andrew, Toby, Tsun-Po Yang, Beyan, Huriya, Whittaker, Pamela, McCann, Owen T., Finer, Sarah, Valdes, Ana M., Leslie, R. David, Deloukas, Panogiotis, and Spector, Timothy D.

Subjects
Methylation -- Analysis, Aging -- Genetic aspects, DNA -- Chemical properties, T cells -- Research, Epigenetic inheritance -- Research, Health
Published
2010

32. Functional diversity for REST (NRSF) is defined by in vivo binding affinity hierarchies at the DNA sequence level

Author

Bruce, Alexander W., Lopez-Contreras, Andres J., Flicek, Paul, Down, Thomas A., Dhami, Pawandeep, Dillon, Shane C., Koch, Christoph M., Langford, Cordelia F., Dunham, Ian, Andrews, Robert M., and Vetrie, David

Subjects
Nucleotide sequence -- Analysis, Biological diversity -- Research, DNA binding proteins -- Research, Mammals -- Genetic aspects, Genetic transcription -- Research, Health
Published
2009

33. An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs)

Author

Rakyan, Vardhman K., Down, Thomas A., Thorne, Natalie P., Flicek, Paul, Kulesha, Eugene, Graf, Stefan, Tomazou, Eleni M., Backdahl, Liselotte, Johnson, Nathan, Herberth, Marlis, Howe, Kevin L., Jackson, David K., Miretti, Marcos M., Fiegler, Heike, Marioni, John C., Birney, Ewan, Hubbard. Tim J.P., Carter, Nigel P., Tavare, Simon, and Beck, Stephan

Subjects
Methylation -- Analysis, Genomics -- Research, DNA -- Chemical properties, Health
Abstract

The article discusses a novel integrated resource, which is used for the genome-wide identification and analysis of the human tissue-specific differentially methylated regions (tDMRs). These tDMRs are shown to play an extremely significant role in the cellular identity and regulation of tissue-specific genome function.

Published
2008

35. Whole-genome sequence-based analysis of thyroid function

Author

Taylor, Peter N., Porcu, Eleonora, Chew, Shelby, Campbell, Purdey J., Traglia, Michela, Brown, Suzanne J., Mullin, Benjamin H., Shihab, Hashem A., Min, Josine, Walter, Klaudia, Memari, Yasin, Huang, Jie, Barnes, Michael R., Beilby, John P., Charoen, Pimphen, Danecek, Petr, Dudbridge, Frank, Forgetta, Vincenzo, Greenwood, Celia, Grundberg, Elin, Johnson, Andrew D., Hui, Jennie, Lim, Ee M., McCarthy, Shane, Muddyman, Dawn, Panicker, Vijay, Perry, John R.B., Bell, Jordana T., Yuan, Wei, Relton, Caroline, Gaunt, Tom, Schlessinger, David, Abecasis, Goncalo, Cucca, Francesco, Surdulescu, Gabriela L., Woltersdorf, Wolfram, Zeggini, Eleftheria, Zheng, Hou-Feng, Toniolo, Daniela, Dayan, Colin M., Naitza, Silvia, Walsh, John P., Spector, Tim, Davey Smith, George, Durbin, Richard, Brent Richards, J., Sanna, Serena, Soranzo, Nicole, Timpson, Nicholas J., Wilson, Scott G., Turki, Saeed Al, Anderson, Carl, Anney, Richard, Antony, Dinu, Artigas, Maria Soler, Ayub, Muhammad, Balasubramaniam, Senduran, Barrett, Jeffrey C., Barroso, Inês, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Day-Williams, Aaron, Day, Ian N.M., Down, Thomas, Du, Yuanping, Dunham, Ian, Edkins, Sarah, Ellis, Peter, Evans, David, Faroogi, Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David R., Flicek, Paul, Flyod, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Geihs, Matthias, Geschwind, Daniel, Griffin, Heather, Grozeva, Detelina, Guo, Xueqin, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Howie, Bryan, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Jackson, David K., Jamshidi, Yalda, Jing, Tian, Joyce, Chris, Kaye, Jane, Keane, Thomas, Keogh, Julia, Kemp, John, Kennedy, Karen, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Liang, Jieqin, Lin, Hong, Li, Rui, Li, Yingrui, Liu, Ryan, Lönnqvist, Jouko, Lopes, Margarida, Lotchkova, Valentina, MacArthur, Daniel, Marchini, Jonathan, Maslen, John, Massimo, Mangino, Mathieson, Iain, Marenne, Gaëlle, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew G., McQuillin, Andrew, Metrustry, Sarah, Mitchison, Hannah, Moayyeri, Alireza, Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donnovan, Michael, Onoufriadis, Alexandros, O'Rahilly, Stephen, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Pietilainen, Olli, Plagnol, Vincent, Quaye, Lydia, Quai, Michael A., Raymond, Lucy, Rehnström, Karola, Richards, Brent, Ring, Susan, Ritchie, Graham R.S., Roberts, Nicola, Savage, David B., Scambler, Peter, Schiffels, Stephen, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Sharp, Sally I., Shin, So-Youn, Skuse, David, Small, Kerrin, Southam, Lorraine, Spasic-Boskovic, Olivera, Clair, David St, Stalker, Jim, Stevens, Elizabeth, Pourcian, Beate St, Sun, Jianping, Suvisaari, Jaana, Tachmazidou, Ionna, Tobin, Martin D., Valdes, Ana, Kogelenberg, Margriet Van, Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Elanor, Whyte, Tamieka, Williams, Hywel, Williamson, Kathleen A., Wilson, Crispian, Wong, Kim, Xu, ChangJiang, Yang, Jian, Zhang, Fend, Zhang, Pingbo, Taylor, Peter N., Porcu, Eleonora, Chew, Shelby, Campbell, Purdey J., Traglia, Michela, Brown, Suzanne J., Mullin, Benjamin H., Shihab, Hashem A., Min, Josine, Walter, Klaudia, Memari, Yasin, Huang, Jie, Barnes, Michael R., Beilby, John P., Charoen, Pimphen, Danecek, Petr, Dudbridge, Frank, Forgetta, Vincenzo, Greenwood, Celia, Grundberg, Elin, Johnson, Andrew D., Hui, Jennie, Lim, Ee M., McCarthy, Shane, Muddyman, Dawn, Panicker, Vijay, Perry, John R.B., Bell, Jordana T., Yuan, Wei, Relton, Caroline, Gaunt, Tom, Schlessinger, David, Abecasis, Goncalo, Cucca, Francesco, Surdulescu, Gabriela L., Woltersdorf, Wolfram, Zeggini, Eleftheria, Zheng, Hou-Feng, Toniolo, Daniela, Dayan, Colin M., Naitza, Silvia, Walsh, John P., Spector, Tim, Davey Smith, George, Durbin, Richard, Brent Richards, J., Sanna, Serena, Soranzo, Nicole, Timpson, Nicholas J., Wilson, Scott G., Turki, Saeed Al, Anderson, Carl, Anney, Richard, Antony, Dinu, Artigas, Maria Soler, Ayub, Muhammad, Balasubramaniam, Senduran, Barrett, Jeffrey C., Barroso, Inês, Beales, Phil, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Day-Williams, Aaron, Day, Ian N.M., Down, Thomas, Du, Yuanping, Dunham, Ian, Edkins, Sarah, Ellis, Peter, Evans, David, Faroogi, Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David R., Flicek, Paul, Flyod, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Geihs, Matthias, Geschwind, Daniel, Griffin, Heather, Grozeva, Detelina, Guo, Xueqin, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Howie, Bryan, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Jackson, David K., Jamshidi, Yalda, Jing, Tian, Joyce, Chris, Kaye, Jane, Keane, Thomas, Keogh, Julia, Kemp, John, Kennedy, Karen, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Lek, Monkol, Liang, Jieqin, Lin, Hong, Li, Rui, Li, Yingrui, Liu, Ryan, Lönnqvist, Jouko, Lopes, Margarida, Lotchkova, Valentina, MacArthur, Daniel, Marchini, Jonathan, Maslen, John, Massimo, Mangino, Mathieson, Iain, Marenne, Gaëlle, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew G., McQuillin, Andrew, Metrustry, Sarah, Mitchison, Hannah, Moayyeri, Alireza, Morris, James, Muntoni, Francesco, Northstone, Kate, O'Donnovan, Michael, Onoufriadis, Alexandros, O'Rahilly, Stephen, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Pietilainen, Olli, Plagnol, Vincent, Quaye, Lydia, Quai, Michael A., Raymond, Lucy, Rehnström, Karola, Richards, Brent, Ring, Susan, Ritchie, Graham R.S., Roberts, Nicola, Savage, David B., Scambler, Peter, Schiffels, Stephen, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Sharp, Sally I., Shin, So-Youn, Skuse, David, Small, Kerrin, Southam, Lorraine, Spasic-Boskovic, Olivera, Clair, David St, Stalker, Jim, Stevens, Elizabeth, Pourcian, Beate St, Sun, Jianping, Suvisaari, Jaana, Tachmazidou, Ionna, Tobin, Martin D., Valdes, Ana, Kogelenberg, Margriet Van, Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T.R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Elanor, Whyte, Tamieka, Williams, Hywel, Williamson, Kathleen A., Wilson, Crispian, Wong, Kim, Xu, ChangJiang, Yang, Jian, Zhang, Fend, and Zhang, Pingbo

Abstract

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free ​thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in ​SYN2 (MAF=23.5%, P=6.15 × 10−9) and a new independent variant in ​PDE8B (MAF=10.4%, P=5.94 × 10−14). For FT4, we report a low-frequency variant near ​B4GALT6/​SLC25A52 (MAF=3.2%, P=1.27 × 10−9) tagging a rare ​TTR variant (MAF=0.4%, P=2.14 × 10−11). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in ​NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Published
2015

36. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Author

Huang, Jie, Howie, Bryan, Mccarthy, Shane, Memari, Yasin, Walter, Klaudia, Min, Josine L., Danecek, Petr, Malerba, Giovanni, Trabetti, Elisabetta, Zheng, Hou-feng, Al Turki, Saeed, Amuzu, Antoinette, Anderson, Carl A., Anney, Richard, Antony, Dinu, Artigas, María Soler, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Barroso, Inês, Beales, Phil, Benn, Marianne, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick F., Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Pablo Casas, Juan, Chambers, John C., Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Cocca, Massimiliano, Collier, David A., Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Day, Ian N. M., Day-williams, Aaron, Dedoussis, George, Down, Thomas, Du, Yuanping, Van Duijn, Cornelia M., Dunham, Ian, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evans, David M., Farooqi, I. Sadaf, Fitzpatrick, David R., Flicek, Paul, Floyd, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gasparini, Paolo, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel, Greenwood, Celia, Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey E., Holmans, Peter, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Iotchkova, Valentina, Isaacs, Aaron, Jackson, David K., Jamshidi, Yalda, Johnson, Jon, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Keogh, Julia, Khawaja, Farrah, Kleber, Marcus E., Van Kogelenberg, Margriet, Kolb-kokocinski, Anja, Kooner, Jaspal S., Lachance, Genevieve, Langenberg, Claudia, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Van Leeuwen, Elisabeth M., Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, Luan, Jian'an, Macarthur, Daniel G., Mangino, Massimo, Marenne, Gaëlle, März, Winfried, Maslen, John, Matchan, Angela, Mathieson, Iain, Mcguffin, Peter, Mcintosh, Andrew M., Mckechanie, Andrew G., Mcquillin, Andrew, Metrustry, Sarah, Migone, Nicola, Mitchison, Hannah M., Moayyeri, Alireza, Morris, James, Morris, Richard, Muddyman, Dawn, Muntoni, Francesco, Nordestgaard, Børge, Northstone, Kate, O'donovan, Michael C., O'rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Scott, Robert A., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So-youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, George Davey, Southam, Lorraine, Spasic-boskovic, Olivera, Spector, Timothy D., St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petros, Tachmazidou, Ioanna, Taylor, Rohan, Tian, Jing, Tobin, Martin D., Toniolo, Daniela, Traglia, Michela, Tybjærg-Hansen, Anne, Valdes, Ana M., Vandersteen, Anthony M., Varbo, Anette, Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Eleanor, Whincup, Peter, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zaza, Gianluigi, Zeggini, Eleftheria, Zhang, Feng, Zhang, Pingbo, Zhang, Weihua, Gambaro, Giovanni, Richards, J. Brent, Durbin, Richard, Timpson, Nicholas J., Marchini, Jonathan, Soranzo, Nicole, Huang, Jie, Howie, Bryan, Mccarthy, Shane, Memari, Yasin, Walter, Klaudia, Min, Josine L., Danecek, Petr, Malerba, Giovanni, Trabetti, Elisabetta, Zheng, Hou-feng, Al Turki, Saeed, Amuzu, Antoinette, Anderson, Carl A., Anney, Richard, Antony, Dinu, Artigas, María Soler, Ayub, Muhammad, Bala, Senduran, Barrett, Jeffrey C., Barroso, Inês, Beales, Phil, Benn, Marianne, Bentham, Jamie, Bhattacharya, Shoumo, Birney, Ewan, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick F., Bounds, Rebecca, Boustred, Chris, Breen, Gerome, Calissano, Mattia, Carss, Keren, Pablo Casas, Juan, Chambers, John C., Charlton, Ruth, Chatterjee, Krishna, Chen, Lu, Ciampi, Antonio, Cirak, Sebahattin, Clapham, Peter, Clement, Gail, Coates, Guy, Cocca, Massimiliano, Collier, David A., Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Curtis, David, Daly, Allan, Day, Ian N. M., Day-williams, Aaron, Dedoussis, George, Down, Thomas, Du, Yuanping, Van Duijn, Cornelia M., Dunham, Ian, Edkins, Sarah, Ekong, Rosemary, Ellis, Peter, Evans, David M., Farooqi, I. Sadaf, Fitzpatrick, David R., Flicek, Paul, Floyd, James, Foley, A. Reghan, Franklin, Christopher S., Futema, Marta, Gallagher, Louise, Gasparini, Paolo, Gaunt, Tom R., Geihs, Matthias, Geschwind, Daniel, Greenwood, Celia, Griffin, Heather, Grozeva, Detelina, Guo, Xiaosen, Guo, Xueqin, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey E., Holmans, Peter, Huang, Liren, Hubbard, Tim, Humphries, Steve E., Hurles, Matthew E., Hysi, Pirro, Iotchkova, Valentina, Isaacs, Aaron, Jackson, David K., Jamshidi, Yalda, Johnson, Jon, Joyce, Chris, Karczewski, Konrad J., Kaye, Jane, Keane, Thomas, Kemp, John P., Kennedy, Karen, Kent, Alastair, Keogh, Julia, Khawaja, Farrah, Kleber, Marcus E., Van Kogelenberg, Margriet, Kolb-kokocinski, Anja, Kooner, Jaspal S., Lachance, Genevieve, Langenberg, Claudia, Langford, Cordelia, Lawson, Daniel, Lee, Irene, Van Leeuwen, Elisabeth M., Lek, Monkol, Li, Rui, Li, Yingrui, Liang, Jieqin, Lin, Hong, Liu, Ryan, Lönnqvist, Jouko, Lopes, Luis R., Lopes, Margarida, Luan, Jian'an, Macarthur, Daniel G., Mangino, Massimo, Marenne, Gaëlle, März, Winfried, Maslen, John, Matchan, Angela, Mathieson, Iain, Mcguffin, Peter, Mcintosh, Andrew M., Mckechanie, Andrew G., Mcquillin, Andrew, Metrustry, Sarah, Migone, Nicola, Mitchison, Hannah M., Moayyeri, Alireza, Morris, James, Morris, Richard, Muddyman, Dawn, Muntoni, Francesco, Nordestgaard, Børge, Northstone, Kate, O'donovan, Michael C., O'rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael J., Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy R., Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Payne, Stewart J., Perry, John R. B., Pietilainen, Olli, Plagnol, Vincent, Pollitt, Rebecca C., Povey, Sue, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Ridout, Cheryl K., Ring, Susan, Ritchie, Graham R. S., Roberts, Nicola, Robinson, Rachel L., Savage, David B., Scambler, Peter, Schiffels, Stephan, Schmidts, Miriam, Schoenmakers, Nadia, Scott, Richard H., Scott, Robert A., Semple, Robert K., Serra, Eva, Sharp, Sally I., Shaw, Adam, Shihab, Hashem A., Shin, So-youn, Skuse, David, Small, Kerrin S., Smee, Carol, Smith, George Davey, Southam, Lorraine, Spasic-boskovic, Olivera, Spector, Timothy D., St Clair, David, St Pourcain, Beate, Stalker, Jim, Stevens, Elizabeth, Sun, Jianping, Surdulescu, Gabriela, Suvisaari, Jaana, Syrris, Petros, Tachmazidou, Ioanna, Taylor, Rohan, Tian, Jing, Tobin, Martin D., Toniolo, Daniela, Traglia, Michela, Tybjærg-Hansen, Anne, Valdes, Ana M., Vandersteen, Anthony M., Varbo, Anette, Vijayarangakannan, Parthiban, Visscher, Peter M., Wain, Louise V., Walters, James T. R., Wang, Guangbiao, Wang, Jun, Wang, Yu, Ward, Kirsten, Wheeler, Eleanor, Whincup, Peter, Whyte, Tamieka, Williams, Hywel J., Williamson, Kathleen A., Wilson, Crispian, Wilson, Scott G., Wong, Kim, Xu, Changjiang, Yang, Jian, Zaza, Gianluigi, Zeggini, Eleftheria, Zhang, Feng, Zhang, Pingbo, Zhang, Weihua, Gambaro, Giovanni, Richards, J. Brent, Durbin, Richard, Timpson, Nicholas J., Marchini, Jonathan, and Soranzo, Nicole

Published
2015

37. An overview of Ensembl

Author

Birney, Ewan, Clarke, Laura, Curwen, Val, Cuff, James, Coates, Guy, Andrews, T. Daniel, Chen, Yuan, Caccamo, Mario, Bevan, Paul, Cutts, Tim, Gilbert, James, Gibbins,Brian, Gane, Paul, Fernandez-Suarez, Xose M., Eyras, Eduardo, Down, Thomas;, Hammond, Martin; Hotz, Hans-Rudolf; Iyer, Vivek; Jekosch, Kerstin; Kahari, Andreas; Kasprzyk, Arek, Keefe, Damian; Keenan, Stephen; Lehvaslaiho, Heikki; McVicker, Graham; Melsopp, Craig; Meidl, Patrick; Mongin, Emmanuel; Pettett, Roger; Pottre, Simon; Proctor, Glenn; Rae, Mark, and Searle, Steve; Slater, Guy; Smedley, Damian; Smith, James; Spooner, Will; Stabenau, Arne; Stalker, james; Storey, Roy; Ureta-Vidal, Abel; Woodwark, K. Cara; Cameron, Graham; Durbin, Richard;, Cox, Anthony; Hubbard, Tim; Clamp, Michele

Subjects
Linkage (Genetics) -- Analysis, Nucleotide sequence -- Analysis, Computational biology -- Analysis, Health
Abstract

A bioinformatics project Ensembl organizes biological information around the sequences of large genome and aims at biological integration of data to include other model organisms relevant for understanding human biology. This provides a linkage between equivalent components in different species and classifies the previously elusive functional elements in the gnome.

Published
2004

38. Computational detection and location of transcription start sites in mammalian genomic DNA

Author

Down, Thomas A. and Hubbard, Tim J.P.

Subjects
Genomics -- Research, RNA -- Research, Mammals -- Genetic aspects, Mammals -- Research, Genetic research, Health
Abstract

The transcription start sit where RNA copies are made from sections of DNA genome are defined. In more complex species, these are more common and are active under several conditions.

Published
2002

39. WormBase 2016: expanding to enable helminth genomic research

Author

Howe, Kevin L., primary, Bolt, Bruce J., additional, Cain, Scott, additional, Chan, Juancarlos, additional, Chen, Wen J., additional, Davis, Paul, additional, Done, James, additional, Down, Thomas, additional, Gao, Sibyl, additional, Grove, Christian, additional, Harris, Todd W., additional, Kishore, Ranjana, additional, Lee, Raymond, additional, Lomax, Jane, additional, Li, Yuling, additional, Muller, Hans-Michael, additional, Nakamura, Cecilia, additional, Nuin, Paulo, additional, Paulini, Michael, additional, Raciti, Daniela, additional, Schindelman, Gary, additional, Stanley, Eleanor, additional, Tuli, Mary Ann, additional, Van Auken, Kimberly, additional, Wang, Daniel, additional, Wang, Xiaodong, additional, Williams, Gary, additional, Wright, Adam, additional, Yook, Karen, additional, Berriman, Matthew, additional, Kersey, Paul, additional, Schedl, Tim, additional, Stein, Lincoln, additional, and Sternberg, Paul W., additional

Published
2015
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42. What can we learn from noncoding regions of similarity between genomes?

Author

Down, Thomas A and Hubbard, Tim JP

Subjects
Genomics (q-bio.GN), Base Composition, Genome, Models, Genetic, Genome, Human, Computational Biology, Mice, Artificial Intelligence, Predictive Value of Tests, FOS: Biological sciences, Animals, Humans, Chromosomes, Human, Pair 6, CpG Islands, DNA, Intergenic, Quantitative Biology - Genomics, Sequence Alignment, Research Article
Abstract

Background: In addition to known protein-coding genes, large amount of apparently non-coding sequence are conserved between the human and mouse genomes. It seems reasonable to assume that these conserved regions are more likely to contain functional elements than less-conserved portions of the genome. Here we used a motif-oriented machine learning method to extract the strongest signal from a set of non-coding conserved sequences. Results: We successfully fitted models to reflect the non-coding sequences, and showed that the results were quite consistent for repeated training runs. Using the learned model to scan genomic sequence, we found that it often made predictions close to the start of annotated genes. We compared this method with other published promoter-prediction systems, and show that the set of promoters which are detected by this method seems to be substantially similar to that detected by existing methods. Conclusions: The results presented here indicate that the promoter signal is the strongest single motif-based signal in the non-coding functional fraction of the genome. They also lend support to the belief that there exists a substantial subset of promoter regions which share common features and are detectable by a variety of computational methods., 10 pages, 5 figures

Published
2003

43. Distinct epigenomic features in end-stage failing human hearts

Author

Movassagh, Mehregan, Choy, Mun-Kit, Knowles, David A, Cordeddu, Lina, Haider, Syed, Down, Thomas, Siggens, Lee, Vujic, Ana, Simeoni, Ilenia, Penkett, Chris, Goddard, Martin, Lio, Pietro, Bennett, Martin R, Foo, Roger S-Y, Movassagh, Mehregan, Choy, Mun-Kit, Knowles, David A, Cordeddu, Lina, Haider, Syed, Down, Thomas, Siggens, Lee, Vujic, Ana, Simeoni, Ilenia, Penkett, Chris, Goddard, Martin, Lio, Pietro, Bennett, Martin R, and Foo, Roger S-Y

Abstract

Background— The epigenome refers to marks on the genome, including DNA methylation and histone modifications, that regulate the expression of underlying genes. A consistent profile of gene expression changes in end-stage cardiomyopathy led us to hypothesize that distinct global patterns of the epigenome may also exist. Methods and Results— We constructed genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation (H3K36me3) enrichment for cardiomyopathic and normal human hearts. More than 506 Mb sequences per library were generated by high-throughput sequencing, allowing us to assign methylation scores to ≈28 million CG dinucleotides in the human genome. DNA methylation was significantly different in promoter CpG islands, intragenic CpG islands, gene bodies, and H3K36me3-enriched regions of the genome. DNA methylation differences were present in promoters of upregulated genes but not downregulated genes. H3K36me3 enrichment itself was also significantly different in coding regions of the genome. Specifically, abundance of RNA transcripts encoded by the DUX4 locus correlated to differential DNA methylation and H3K36me3 enrichment. In vitro, Dux gene expression was responsive to a specific inhibitor of DNA methyltransferase, and Dux siRNA knockdown led to reduced cell viability. Conclusions— Distinct epigenomic patterns exist in important DNA elements of the cardiac genome in human end-stage cardiomyopathy. The epigenome may control the expression of local or distal genes with critical functions in myocardial stress response. If epigenomic patterns track with disease progression, assays for the epigenome may be useful for assessing prognosis in heart failure. Further studies are needed to determine whether and how the epigenome contributes to the development of cardiomyopathy.

Published
2011

44. DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta

Author

Novakovic, Boris, Wong, Nick C, Sibson, Mandy, Ng, Hong-Kiat, Morley, Ruth, Manuelpillai, Ursula, Down, Thomas, Rakyan, Vardhman K, Beck, Stephan, Hiendleder, Stefan, Roberts, Claire T, Craig, Jeffrey M, Saffery, Richard, Novakovic, Boris, Wong, Nick C, Sibson, Mandy, Ng, Hong-Kiat, Morley, Ruth, Manuelpillai, Ursula, Down, Thomas, Rakyan, Vardhman K, Beck, Stephan, Hiendleder, Stefan, Roberts, Claire T, Craig, Jeffrey M, and Saffery, Richard

Published
2010

45. Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure

Author

Movassagh, Mehregan, Choy, Mun-Kit, Goddard, Martin, Bennett, Martin R, Down, Thomas A, Foo, Roger S-Y, Movassagh, Mehregan, Choy, Mun-Kit, Goddard, Martin, Bennett, Martin R, Down, Thomas A, and Foo, Roger S-Y

Abstract

Epigenetic mechanisms such as microRNA and histone modification are crucially responsible for dysregulated gene expression in heart failure. In contrast, the role of DNA methylation, another well-characterized epigenetic mark, is unknown. In order to examine whether human cardiomyopathy of different etiologies are connected by a unifying pattern of DNA methylation pattern, we undertook profiling with ischaemic and idiopathic end-stage cardiomyopathic left ventricular (LV) explants from patients who had undergone cardiac transplantation compared to normal control. We performed a preliminary analysis using methylated-DNA immunoprecipitation-chip (MeDIP-chip), validated differential methylation loci by bisulfite-(BS) PCR and high throughput sequencing, and identified 3 angiogenesis-related genetic loci that were differentially methylated. Using quantitative RT-PCR, we found that the expression of these genes differed significantly between CM hearts and normal control (p<0.01). Moreover, for each individual LV tissue, differential methylation showed a predicted correlation to differential expression of the corresponding gene. Thus, differential DNA methylation exists in human cardiomyopathy. In this series of heterogeneous cardiomyopathic LV explants, differential DNA methylation was found in at least 3 angiogenesis-related genes. While in other systems, changes in DNA methylation at specific genomic loci usually precede changes in the expression of corresponding genes, our current findings in cardiomyopathy merit further investigation to determine whether DNA methylation changes play a causative role in the progression of heart failure.

Published
2010

46. Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface

Author

Novakovic, Boris, Sibson, Mandy, Ng, Hong Kiat, Manuelpillai, Ursula, Rakyan, Vardhman, Down, Thomas, Beck, Stephan, Fournier, Thierry, Evain-Brion, Danielle, Dimitriadis, Eva, Craig, Jeffrey M, Morley, Ruth, Saffery, Richard, Novakovic, Boris, Sibson, Mandy, Ng, Hong Kiat, Manuelpillai, Ursula, Rakyan, Vardhman, Down, Thomas, Beck, Stephan, Fournier, Thierry, Evain-Brion, Danielle, Dimitriadis, Eva, Craig, Jeffrey M, Morley, Ruth, and Saffery, Richard

Published
2009

50. 1032 Host-Environment Interactions Shape the Risk for Ulcerative Colitis: Results From a Twin Epigenome-Wide Association Study

Author

Haesler, Robert, primary, Feng, Zhe, additional, Bäckdahl, Liselotte, additional, Spehlmann, Martina E., additional, Franke, Andre, additional, Teschendorff, Andrew, additional, Rakyan, Vardhman, additional, Down, Thomas A., additional, Wilson, Gareth A., additional, Feber, Andrew, additional, Beck, Stephan, additional, Schreiber, Stefan, additional, and Rosenstiel, Philip C., additional

Published
2013
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