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1. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

Author

McDonagh, Ellen M, Rueda, Antonio, Polychronopoulos, Dimitris, Chan, Georgia, Angus-Leppan, Heather, Bhatia, Kailash P, Davison, James E, Festenstein, Richard, Fratta, Pietro, Giunti, Paola, Howard, Robin, Venkata, Laxmi, Laurá, Matilde, McEntagart, Meriel, Menzies, Lara, Morris, Huw, Reilly, Mary M, Robinson, Robert, Rosser, Elisabeth, Faravelli, Francesca, Schrag, Anette, Schott, Jonathan M, Warner, Thomas T, Wood, Nicholas W, Bourn, David, Eggleton, Kelly, Labrum, Robyn, Twiss, Philip, Abbs, Stephen, Santos, Liana, Almheiri, Ghareesa, Sheikh, Isabella, Vandrovcova, Jana, Patch, Christine, Taylor Tavares, Ana Lisa, Hyder, Zerin, Need, Anna, Brittain, Helen, Baple, Emma, Moutsianas, Loukas, Deshpande, Viraj, Perry, Denise L, Ajay, Subramanian S., Chawla, Aditi, Rajan, Vani, Oprych, Kathryn, Chinnery, Patrick F, Douglas, Angela, Wilson, Gill, Ellard, Sian, Temple, I Karen, Mumford, Andrew, McMullan, Dom, Naresh, Kikkeri, Flinter, Frances A, Taylor, Jenny C, Greenhalgh, Lynn, Newman, William, Brennan, Paul, Sayer, John A, Raymond, F Lucy, Chitty, Lyn S, Ambrose, John C., Arumugam, Prabhu, Bleda, Marta, Boardman-Pretty, Freya, Boissiere, Jeanne M., Boustred, Christopher R., Craig, Clare E.H., de Burca, Anna, Devereau, Andrew, Elgar, Greg, Foulger, Rebecca E., Furió-Tarí, Pedro, Hackett, Joanne, Halai, Dina, Hamblin, Angela, Henderson, Shirley, Holman, James, Hubbard, Tim J.P., Jackson, Rob, Jones, Louise J., Kayikci, Melis, Lahnstein, Lea, Lawson, Kay, Leigh, Sarah E.A., Leong, Ivonne U.S., Lopez, Javier F., Maleady-Crowe, Fiona, Mason, Joanne, Mueller, Michael, Murugaesu, Nirupa, Odhams, Chris A., Perez-Gil, Daniel, Pullinger, John, Rahim, Tahrima, Riesgo-Ferreiro, Pablo, Rogers, Tim, Ryten, Mina, Savage, Kevin, Sawant, Kushmita, Siddiq, Afshan, Sieghart, Alexander, Smedley, Damian, Sosinsky, Alona, Spooner, William, Stevens, Helen E., Stuckey, Alexander, Sultana, Razvan, Thompson, Simon R., Tregidgo, Carolyn, Walsh, Emma, Watters, Sarah A., Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Zarowiecki, Magdalena, Ibañez, Kristina, Polke, James, Hagelstrom, R Tanner, Dolzhenko, Egor, Pasko, Dorota, Thomas, Ellen Rachel Amy, Daugherty, Louise C, Kasperaviciute, Dalia, Smith, Katherine R, Deans, Zandra C, Hill, Sue, Fowler, Tom, Scott, Richard H, Hardy, John, Houlden, Henry, Rendon, Augusto, Caulfield, Mark J, Eberle, Michael A, Taft, Ryan J, and Tucci, Arianna

Published
2022
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2. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

Adeleye, Adelani, Alba, Camille, Bacikova, Dagmar, Hupalo, Daniel N., Martinez, Elisa McGrath, Pollard, Harvey B., Sukumar, Gauthaman, Soltis, Anthony R., Tuck, Meila, Zhang, Xijun, Wilkerson, Matthew D., Smith, Bradley N., Ticozzi, Nicola, Fallini, Claudia, Gkazi, Athina Soragia, Topp, Simon D., Kost, Jason, Scotter, Emma L., Kenna, Kevin P., Miller, Jack W., Tiloca, Cinzia, Vance, Caroline, Danielson, Eric W., Troakes, Claire, Colombrita, Claudia, Al-Sarraj, Safa, Lewis, Elizabeth A., King, Andrew, Calini, Daniela, Pensato, Viviana, Castellotti, Barbara, de Belleroche, Jacqueline, Baas, Frank, ten Asbroek, Anneloor L.M.A., Sapp, Peter C., McKenna-Yasek, Diane, McLaughlin, Russell L., Polak, Meraida, Asress, Seneshaw, Esteban-Pérez, Jesús, Muñoz-Blanco, José Luis, Stevic, Zorica, D’Alfonso, Sandra, Mazzini, Letizia, Comi, Giacomo P., Del Bo, Roberto, Ceroni, Mauro, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, van Rheenen, Wouter, Diekstra, Frank P., Rademakers, Rosa, van Blitterswijk, Marka, Boylan, Kevin B., Lauria, Giuseppe, Duga, Stefano, Corti, Stefania, Cereda, Cristina, Corrado, Lucia, Sorarù, Gianni, Williams, Kelly L., Nicholson, Garth A., Blair, Ian P., Leblond-Manry, Claire, Rouleau, Guy A., Hardiman, Orla, Morrison, Karen E., Veldink, Jan H., van den Berg, Leonard H., Al-Chalabi, Ammar, Pall, Hardev, Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Taroni, Franco, García-Redondo, Alberto, Wu, Zheyang, Gellera, Cinzia, Ratti, Antonia, Brown, Robert H., Jr., Shaw, Christopher E., Ambrose, John C., Arumugam, Prabhu, Baple, Emma L., Bleda, Marta, Boardman-Pretty, Freya, Boissiere, Jeanne M., Boustred, Christopher R., Brittain, H., Caulfield, Mark J., Chan, Georgia C., Craig, Clare E.H., Daugherty, Louise C., de Burca, Anna, Devereau, Andrew, Elgar, Greg, Foulger, Rebecca E., Fowler, Tom, Furió-Tarí, Pedro, Hackett, Joanne M., Halai, Dina, Hamblin, Angela, Henderson, Shirley, Holman, James E., Hubbard, Tim J.P., Jackson, Rob, Jones, Louise J., Kasperaviciute, Dalia, Kayikci, Melis, Lahnstein, Lea, Lawson, Kay, Leigh, Sarah E.A., Leong, Ivonne U.S., Lopez, Javier F., Maleady-Crowe, Fiona, Mason, Joanne, McDonagh, Ellen M., Moutsianas, Loukas, Mueller, Michael, Murugaesu, Nirupa, Need, Anna C., Odhams, Chris A., Patch, Christine, Perez-Gil, Daniel, Polychronopoulos, Dimitris, Pullinger, John, Rahim, Tahrima, Rendon, Augusto, Riesgo-Ferreiro, Pablo, Rogers, Tim, Savage, Kevin, Sawant, Kushmita, Scott, Richard H., Siddiq, Afshan, Sieghart, Alexander, Smedley, Damian, Smith, Katherine R., Sosinsky, Alona, Spooner, William, Stevens, Helen E., Stuckey, Alexander, Sultana, Razvan, Thomas, Ellen R.A., Thompson, Simon R., Tregidgo, Carolyn, Walsh, Emma, Watters, Sarah A., Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Zarowiecki, Magdalena, Arepalli, Sampath, Auluck, Pavan, Baloh, Robert H., Bowser, Robert, Brice, Alexis, Broach, James, Camu, William, Chiò, Adriano, Cooper-Knock, John, Corcia, Philippe, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Faghri, Faraz, Farren, Jennifer, Feldman, Eva, Floeter, Mary Kay, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Goutman, Stephen A., Heiman-Patterson, Terry D., Hernandez, Dena G., Hoover, Ben, Jansson, Lilja, Kamel, Freya, Kirby, Janine, Kowall, Neil W., Laaksovirta, Hannu, Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel JL., Maragakis, Nicholas J., Mora, Gabriele, Mouzat, Kevin, Myllykangas, Liisa, Nalls, Mike A., Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Renton, Alan E., Robberecht, Wim, Robey, Ian, Rogaeva, Ekaterina, Rothstein, Jeffrey D., Sendtner, Michael, Sidle, Katie C., Simmons, Zachary, Stone, David J., Tienari, Pentti J., Trojanowski, John Q., Troncoso, Juan C., Valori, Miko, Van Damme, Philip, Van Den Bosch, Ludo, Zinman, Lorne, Albani, Diego, Borroni, Barbara, Padovani, Alessandro, Bruni, Amalia, Clarimon, Jordi, Dols-Icardo, Oriol, Illán-Gala, Ignacio, Lleó, Alberto, Danek, Adrian, Galimberti, Daniela, Scarpini, Elio, Serpente, Maria, Graff, Caroline, Chiang, Huei-Hsin, Khoshnood, Behzad, Öijerstedt, Linn, Morris, Christopher M., Nacmias, Benedetta, Sorbi, Sandro, Nielsen, Jorgen E., Hjermind, Lynne E., Novelli, Valeria, Puca, Annibale A., Pastor, Pau, Alvarez, Ignacio, Diez-Fairen, Monica, Aguilar, Miquel, Perneczky, Robert, Diehl-Schimd, Janine, Rossi, Mina, Ruiz, Agustin, Boada, Mercè, Hernández, Isabel, Moreno-Grau, Sonia, Schlachetzki, Johannes C., Aarsland, Dag, Albert, Marilyn S., Attems, Johannes, Barrett, Matthew J., Beach, Thomas G., Bekris, Lynn M., Bennett, David A., Besser, Lilah M., Bigio, Eileen H., Black, Sandra E., Boeve, Bradley F., Bohannan, Ryan C., Brett, Francesca, Brunetti, Maura, Caraway, Chad A., Palma, Jose-Alberto, Calvo, Andrea, Canosa, Antonio, Dickson, Dennis, Duyckaerts, Charles, Faber, Kelley, Ferman, Tanis, Flanagan, Margaret E., Floris, Gianluca, Foroud, Tatiana M., Fortea, Juan, Gan-Or, Ziv, Gentleman, Steve, Ghetti, Bernardino, Gibbs, Jesse Raphael, Goate, Alison, Goldstein, David, González-Aramburu, Isabel, Graff-Radford, Neill R., Hodges, Angela K., Hu, Heng-Chen, Hupalo, Daniel, Infante, Jon, Iranzo, Alex, Kaiser, Scott M., Kaufmann, Horacio, Keith, Julia, Kim, Ronald C., Klein, Gregory, Krüger, Rejko, Kukull, Walter, Kuzma, Amanda, Lage, Carmen, Lesage, Suzanne, Leverenz, James B., Logroscino, Giancarlo, Lopez, Grisel, Love, Seth, Mao, Qinwen, Marti, Maria Jose, Martinez-McGrath, Elisa, Masellis, Mario, Masliah, Eliezer, May, Patrick, McKeith, Ian, Mesulam, Marek-Marsel, Monuki, Edwin S., Newell, Kathy L., Norcliffe-Kaufmann, Lucy, Palmer, Laura, Perkins, Matthew, Pletnikova, Olga, Molina-Porcel, Laura, Reynolds, Regina H., Rodríguez-Rodríguez, Eloy, Rohrer, Jonathan D., Sanchez-Juan, Pascual, Scherzer, Clemens R., Serrano, Geidy E., Shakkottai, Vikram, Sidransky, Ellen, Tayebi, Nahid, Thomas, Alan J., Tilley, Bension S., Walton, Ronald L., Woltjer, Randy, Wszolek, Zbigniew K., Xiromerisiou, Georgia, Zecca, Chiara, Phatnani, Hemali, Kwan, Justin, Sareen, Dhruv, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Shneider, Neil A., Fraenkel, Ernest, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos.A., Butovsky, Oleg, Dubnau, Joshua, Nath, Avindra, Harms, Matt, Aronica, Eleonora, Poss, Mary, Phillips-Cremins, Jennifer, Crary, John, Atassi, Nazem, Lange, Dale J., Adams, Darius J., Stefanis, Leonidas, Gotkine, Marc, Babu, Suma, Raj, Towfique, Paganoni, Sabrina, Shalem, Ophir, Smith, Colin, Zhang, Bin, Harris, Brent, Broce, Iris, Drory, Vivian, Ravits, John, McMillan, Corey, Menon, Vilas, Wu, Lani, Altschuler, Steven, Amar, Khaled, Archibald, Neil, Bandmann, Oliver, Capps, Erica, Church, Alistair, Coebergh, Jan, Costantini, Alyssa, Critchley, Peter, Ghosh, Boyd CP., Hu, Michele T.M., Kobylecki, Christopher, Leigh, P. Nigel, Mann, Carl, Massey, Luke A., Morris, Huw R., Nath, Uma, Pavese, Nicola, Paviour, Dominic, Sharma, Jagdish, Vaughan, Jenny, Dewan, Ramita, Chia, Ruth, Ding, Jinhui, Hickman, Richard A., Stein, Thor D., Abramzon, Yevgeniya, Ahmed, Sarah, Sabir, Marya S., Portley, Makayla K., Tucci, Arianna, Ibáñez, Kristina, Shankaracharya, F.N.U., Keagle, Pamela, Rossi, Giacomina, Caroppo, Paola, Tagliavini, Fabrizio, Waldo, Maria L., Johansson, Per M., Nilsson, Christer F., Rowe, James B., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Jabbari, Edwin, Viollet, Coralie, Glass, Jonathan D., Singleton, Andrew B., Silani, Vincenzo, Ross, Owen A., Ryten, Mina, Torkamani, Ali, Tanaka, Toshiko, Ferrucci, Luigi, Resnick, Susan M., Pickering-Brown, Stuart, Brady, Christopher B., Kowal, Neil, Hardy, John A., Van Deerlin, Vivianna, Vonsattel, Jean Paul, Harms, Matthew B., Ferrari, Raffaele, Landers, John E., Gibbs, J. Raphael, Dalgard, Clifton L., Scholz, Sonja W., and Traynor, Bryan J.

Published
2021
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3. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author

Barclay, Murray, Peyrin-Biroulet, Laurent, Chamaillard, Mathias, Colombel, Jean-Frederick, Cottone, Mario, Croft, Anthony, D’Incà, Renata, Halfvarson, Jonas, Hanigan, Katherine, Henderson, Paul, Hugot, Jean-Pierre, Karban, Amir, Kennedy, Nicholas A., Khan, Mohammed Azam, Lémann, Marc, Levine, Arie, Massey, Dunecan, Milla, Monica, Montgomery, Grant W., Ng, Sok Meng Evelyn, Oikonomou, Ioannis, Peeters, Harald, Proctor, Deborah D., Rahier, Jean-Francois, Roberts, Rebecca, Rutgeerts, Paul, Seibold, Frank, Stronati, Laura, Taylor, Kirstin M., Törkvist, Leif, Ublick, Kullak, Van Limbergen, Johan, Van Gossum, Andre, Vatn, Morten H., Zhang, Hu, Zhang, Wei, Andrews, Jane M., Bampton, Peter A., Florin, Timothy H., Gearry, Richard, Krishnaprasad, Krupa, Lawrance, Ian C., Mahy, Gillian, Radford-Smith, Graham, Roberts, Rebecca L., Simms, Lisa A., Amininijad, Leila, Cleynen, Isabelle, Dewit, Olivier, Franchimont, Denis, Georges, Michel, Laukens, Debby, Theatre, Emilie, Van Gossum, André, Vermeire, Severine, Aumais, Guy, Baidoo, Leonard, Barrie, Arthur M., III, Beck, Karen, Bernard, Edmond-Jean, Binion, David G., Bitton, Alain, Brant, Steve R., Cho, Judy H., Cohen, Albert, Croitoru, Kenneth, Daly, Mark J., Datta, Lisa W., Deslandres, Colette, Duerr, Richard H., Dutridge, Debra, Ferguson, John, Fultz, Joann, Goyette, Philippe, Greenberg, Gordon R., Haritunians, Talin, Jobin, Gilles, Katz, Seymour, Lahaie, Raymond G., McGovern, Dermot P., Nelson, Linda, Ng, Sok Meng, Ning, Kaida, Paré, Pierre, Regueiro, Miguel D., Rioux, John D., Ruggiero, Elizabeth, Schumm, L. Philip, Schwartz, Marc, Scott, Regan, Sharma, Yashoda, Silverberg, Mark S., Spears, Denise, Steinhart, A. Hillary, Stempak, Joanne M., Swoger, Jason M., Tsagarelis, Constantina, Zhang, Clarence, Zhao, Hongyu, Aerts, Jan, Ahmad, Tariq, Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barnes, Chris, Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Cardin, Niall, Clee, Chris M., Coffey, Alison J., Connell, John M.C., Conrad, Donald F., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, I, Ferrier, Nicol, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Frayling, Timothy M., Freathy, Rachel M., Giannoulatou, Eleni, Gibbs, Polly, Gilbert, Paul, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A., Hocking, Lynne, Holmes, Chris, Howard, Eleanor, Howard, Philip, Howson, Joanna M.M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Lathrop, G. Mark, Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Marchini, Jonathan L., Martin, Paul, Massey, Dunecan C.O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., McVean, Gil, Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Munroe, Patricia B., Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Palotie, Aarno, Parnell, Kirstie, Pearson, Richard, Pernet, David, Perry, John R.B., Phillips, Anne, Plagnol, Vincent, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Robson, Samuel, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Sawcer, Stephen J., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stirrups, Kathy, Stone, Millicent A., Strachan, David P., Su, Zhan, Symmons, Deborah P.M., Thompson, John R., Thomson, Wendy, Tobin, Martin D., Travers, Mary E., Turnbull, Clare, Vukcevic, Damjan, Wain, Louise V., Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Yau, Chris, Young, Allan H., Zeggini, Eleftheria, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C.L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V.S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Hurles, Matthew E., Duncanson, Audrey, Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., Kwiatkowski, Dominic P., McCarthy, Mark I., Craddock, Nick, Deloukas, Panos, Donnelly, Peter, Blackwell, Jenefer M., Bramon, Elvira, Casas, Juan P., Corvin, Aiden, Jankowski, Janusz, Markus, Hugh S., Palmer, Colin N.A., Plomin, Robert, Rautanen, Anna, Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C.A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Pirinen, Matti, Strange, Amy, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Bodea, Corneliu A., Neale, Benjamin M., Ripke, Stephan, Devlin, Bernie, and Roeder, Kathryn

Published
2016
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4. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

Author

Ibañez, Kristina, primary, Polke, James, additional, Hagelstrom, R Tanner, additional, Dolzhenko, Egor, additional, Pasko, Dorota, additional, Thomas, Ellen Rachel Amy, additional, Daugherty, Louise C, additional, Kasperaviciute, Dalia, additional, Smith, Katherine R, additional, Deans, Zandra C, additional, Hill, Sue, additional, Fowler, Tom, additional, Scott, Richard H, additional, Hardy, John, additional, Chinnery, Patrick F, additional, Houlden, Henry, additional, Rendon, Augusto, additional, Caulfield, Mark J, additional, Eberle, Michael A, additional, Taft, Ryan J, additional, Tucci, Arianna, additional, McDonagh, Ellen M, additional, Rueda, Antonio, additional, Polychronopoulos, Dimitris, additional, Chan, Georgia, additional, Angus-Leppan, Heather, additional, Bhatia, Kailash P, additional, Davison, James E, additional, Festenstein, Richard, additional, Fratta, Pietro, additional, Giunti, Paola, additional, Howard, Robin, additional, Venkata, Laxmi, additional, Laurá, Matilde, additional, McEntagart, Meriel, additional, Menzies, Lara, additional, Morris, Huw, additional, Reilly, Mary M, additional, Robinson, Robert, additional, Rosser, Elisabeth, additional, Faravelli, Francesca, additional, Schrag, Anette, additional, Schott, Jonathan M, additional, Warner, Thomas T, additional, Wood, Nicholas W, additional, Bourn, David, additional, Eggleton, Kelly, additional, Labrum, Robyn, additional, Twiss, Philip, additional, Abbs, Stephen, additional, Santos, Liana, additional, Almheiri, Ghareesa, additional, Sheikh, Isabella, additional, Vandrovcova, Jana, additional, Patch, Christine, additional, Taylor Tavares, Ana Lisa, additional, Hyder, Zerin, additional, Need, Anna, additional, Brittain, Helen, additional, Baple, Emma, additional, Moutsianas, Loukas, additional, Deshpande, Viraj, additional, Perry, Denise L, additional, Ajay, Subramanian S., additional, Chawla, Aditi, additional, Rajan, Vani, additional, Oprych, Kathryn, additional, Douglas, Angela, additional, Wilson, Gill, additional, Ellard, Sian, additional, Temple, I Karen, additional, Mumford, Andrew, additional, McMullan, Dom, additional, Naresh, Kikkeri, additional, Flinter, Frances A, additional, Taylor, Jenny C, additional, Greenhalgh, Lynn, additional, Newman, William, additional, Brennan, Paul, additional, Sayer, John A, additional, Raymond, F Lucy, additional, Chitty, Lyn S, additional, Ambrose, John C., additional, Arumugam, Prabhu, additional, Bleda, Marta, additional, Boardman-Pretty, Freya, additional, Boissiere, Jeanne M., additional, Boustred, Christopher R., additional, Craig, Clare E.H., additional, de Burca, Anna, additional, Devereau, Andrew, additional, Elgar, Greg, additional, Foulger, Rebecca E., additional, Furió-Tarí, Pedro, additional, Hackett, Joanne, additional, Halai, Dina, additional, Hamblin, Angela, additional, Henderson, Shirley, additional, Holman, James, additional, Hubbard, Tim J.P., additional, Jackson, Rob, additional, Jones, Louise J., additional, Kayikci, Melis, additional, Lahnstein, Lea, additional, Lawson, Kay, additional, Leigh, Sarah E.A., additional, Leong, Ivonne U.S., additional, Lopez, Javier F., additional, Maleady-Crowe, Fiona, additional, Mason, Joanne, additional, Mueller, Michael, additional, Murugaesu, Nirupa, additional, Odhams, Chris A., additional, Perez-Gil, Daniel, additional, Pullinger, John, additional, Rahim, Tahrima, additional, Riesgo-Ferreiro, Pablo, additional, Rogers, Tim, additional, Ryten, Mina, additional, Savage, Kevin, additional, Sawant, Kushmita, additional, Siddiq, Afshan, additional, Sieghart, Alexander, additional, Smedley, Damian, additional, Sosinsky, Alona, additional, Spooner, William, additional, Stevens, Helen E., additional, Stuckey, Alexander, additional, Sultana, Razvan, additional, Thompson, Simon R., additional, Tregidgo, Carolyn, additional, Walsh, Emma, additional, Watters, Sarah A., additional, Welland, Matthew J., additional, Williams, Eleanor, additional, Witkowska, Katarzyna, additional, Wood, Suzanne M., additional, and Zarowiecki, Magdalena, additional

Published
2022
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6. Common genetic determinants of vitamin D insufficiency: a genome-wide association study

Author

Wang, Thomas J, Zhang, Feng, Richards, J Brent, Kestenbaum, Bryan, van Meurs, Joyce B, Berry, Diane, Kiel, Douglas P, Streeten, Elizabeth A, Ohlsson, Claes, Koller, Daniel L, Peltonen, Leena, Cooper, Jason D, O'Reilly, Paul F, Houston, Denise K, Glazer, Nicole L, Vandenput, Liesbeth, Peacock, Munro, Shi, Julia, Rivadeneira, Fernando, McCarthy, Mark I, Anneli, Pouta, de Boer, Ian H, Mangino, Massimo, Kato, Bernet, Smyth, Deborah J, Booth, Sarah L, Jacques, Paul F, Burke, Greg L, Goodarzi, Mark, Cheung, Ching-Lung, Wolf, Myles, Rice, Kenneth, Goltzman, David, Hidiroglou, Nick, Ladouceur, Martin, Wareham, Nicholas J, Hocking, Lynne J, Hart, Deborah, Arden, Nigel K, Cooper, Cyrus, Malik, Suneil, Fraser, William D, Hartikainen, Anna-Liisa, Zhai, Guangju, Macdonald, Helen M, Forouhi, Nita G, Loos, Ruth JF, Reid, David M, Hakim, Alan, Dennison, Elaine, Liu, Yongmei, Power, Chris, Stevens, Helen E, Jaana, Laitinen, Vasan, Ramachandran S, Soranzo, Nicole, Bojunga, Jörg, Psaty, Bruce M, Lorentzon, Mattias, Foroud, Tatiana, Harris, Tamara B, Hofman, Albert, Jansson, John-Olov, Cauley, Jane A, Uitterlinden, Andre G, Gibson, Quince, Järvelin, Marjo-Riitta, Karasik, David, Siscovick, David S, Econs, Michael J, Kritchevsky, Stephen B, Florez, Jose C, Todd, John A, Dupuis, Josee, Hyppönen, Elina, and Spector, Timothy D

Published
2010
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7. Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

Author

Jones, Christine L., Degasperi, Andrea, Grandi, Vieri, Amarante, Tauanne D., Mitchell, Tracey J., Nik-Zainal, Serena, Whittaker, Sean J., Ambrose, John C., Arumugam, Prabhu, Baple, Emma L., Bleda, Marta, Boardman-Pretty, Freya, Boissiere, Jeanne M., Boustred, Christopher R., Brittain, Helen, Caulfield, Mark J., Chan, Georgia C., Craig, Clare E. H., Daugherty, Louise C., De Burca, Anna, Devereau, Andrew, Elgar, Greg, Foulger, Rebecca E., Fowler, Tom, Furió-Tarí, Pedro, Giess, Adam, Hackett, Joanne M., Halai, Dina, Hamblin, Angela, Henderson, Shirley, Holman, James E., Hubbard, Tim J. P., Ibáñez, Kristina, Jackson, Rob, Jones, Louise J., Kasperaviciute, Dalia, Kayikci, Melis, Kousathanas, Athanasios, Lahnstein, Lea, Lawson, Kay, Leigh, Sarah E. A., Leong, Ivonne U. S., Lopez, Javier F., Maleady-Crowe, Fiona, Mason, Joanne, McDonagh, Ellen M., Moutsianas, Loukas, Mueller, Michael, Murugaesu, Nirupa, Need, Anna C., O’Donovan, Peter, Odhams, Chris A., Orioli, Andrea, Patch, Christine, Pereira, Mariana Buongermino, Perez-Gil, Daniel, Polychronopoulos, Dimitris, Pullinger, John, Rahim, Tahrima, Rendon, Augusto, Riesgo-Ferreiro, Pablo, Rogers, Tim, Ryten, Mina, Savage, Kevin, Sawant, Kushmita, Scott, Richard H., Siddiq, Afshan, Sieghart, Alexander, Smedley, Damian, Smith, Katherine R., Smith, Samuel C., Sosinsky, Alona, Spooner, William, Stevens, Helen E., Stuckey, Alexander, Sultana, Razvan, Tanguy, Mélanie, Thomas, Ellen R. A., Thompson, Simon R., Tregidgo, Carolyn, Tucci, Arianna, Walsh, Emma, Watters, Sarah A., Welland, Matthew J., Williams, Eleanor, Witkowska, Katarzyna, Wood, Suzanne M., Zarowiecki, Magdalena, and Apollo - University of Cambridge Repository

Subjects
hemic and lymphatic diseases, article, 631/67/69, 631/67/1990/291/1621/1916
Abstract

Funder: Galderma; doi: http://dx.doi.org/10.13039/501100009754, Funder: NIHR-BRC Cambridge core grant, Funder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272, Funder: NHS England, T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin’s T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma.

Published
2021

8. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Author

Nejentsev, Sergey, Howson, Joanna M.M., Walker, Neil M., Szeszko, Jeffrey, Fields, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., and Todd, John A.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as [...]

Published
2007

9. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author

Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]

Published
2007
Full Text
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10. Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Author

Dewan, Ramita, primary, Chia, Ruth, additional, Ding, Jinhui, additional, Hickman, Richard A., additional, Stein, Thor D., additional, Abramzon, Yevgeniya, additional, Ahmed, Sarah, additional, Sabir, Marya S., additional, Portley, Makayla K., additional, Tucci, Arianna, additional, Ibáñez, Kristina, additional, Shankaracharya, F.N.U., additional, Keagle, Pamela, additional, Rossi, Giacomina, additional, Caroppo, Paola, additional, Tagliavini, Fabrizio, additional, Waldo, Maria L., additional, Johansson, Per M., additional, Nilsson, Christer F., additional, Rowe, James B., additional, Benussi, Luisa, additional, Binetti, Giuliano, additional, Ghidoni, Roberta, additional, Jabbari, Edwin, additional, Viollet, Coralie, additional, Glass, Jonathan D., additional, Singleton, Andrew B., additional, Silani, Vincenzo, additional, Ross, Owen A., additional, Ryten, Mina, additional, Torkamani, Ali, additional, Tanaka, Toshiko, additional, Ferrucci, Luigi, additional, Resnick, Susan M., additional, Pickering-Brown, Stuart, additional, Brady, Christopher B., additional, Kowal, Neil, additional, Hardy, John A., additional, Van Deerlin, Vivianna, additional, Vonsattel, Jean Paul, additional, Harms, Matthew B., additional, Morris, Huw R., additional, Ferrari, Raffaele, additional, Landers, John E., additional, Chiò, Adriano, additional, Gibbs, J. Raphael, additional, Dalgard, Clifton L., additional, Scholz, Sonja W., additional, Traynor, Bryan J., additional, Adeleye, Adelani, additional, Alba, Camille, additional, Bacikova, Dagmar, additional, Hupalo, Daniel N., additional, Martinez, Elisa McGrath, additional, Pollard, Harvey B., additional, Sukumar, Gauthaman, additional, Soltis, Anthony R., additional, Tuck, Meila, additional, Zhang, Xijun, additional, Wilkerson, Matthew D., additional, Smith, Bradley N., additional, Ticozzi, Nicola, additional, Fallini, Claudia, additional, Gkazi, Athina Soragia, additional, Topp, Simon D., additional, Kost, Jason, additional, Scotter, Emma L., additional, Kenna, Kevin P., additional, Miller, Jack W., additional, Tiloca, Cinzia, additional, Vance, Caroline, additional, Danielson, Eric W., additional, Troakes, Claire, additional, Colombrita, Claudia, additional, Al-Sarraj, Safa, additional, Lewis, Elizabeth A., additional, King, Andrew, additional, Calini, Daniela, additional, Pensato, Viviana, additional, Castellotti, Barbara, additional, de Belleroche, Jacqueline, additional, Baas, Frank, additional, ten Asbroek, Anneloor L.M.A., additional, Sapp, Peter C., additional, McKenna-Yasek, Diane, additional, McLaughlin, Russell L., additional, Polak, Meraida, additional, Asress, Seneshaw, additional, Esteban-Pérez, Jesús, additional, Muñoz-Blanco, José Luis, additional, Stevic, Zorica, additional, D’Alfonso, Sandra, additional, Mazzini, Letizia, additional, Comi, Giacomo P., additional, Del Bo, Roberto, additional, Ceroni, Mauro, additional, Gagliardi, Stella, additional, Querin, Giorgia, additional, Bertolin, Cinzia, additional, van Rheenen, Wouter, additional, Diekstra, Frank P., additional, Rademakers, Rosa, additional, van Blitterswijk, Marka, additional, Boylan, Kevin B., additional, Lauria, Giuseppe, additional, Duga, Stefano, additional, Corti, Stefania, additional, Cereda, Cristina, additional, Corrado, Lucia, additional, Sorarù, Gianni, additional, Williams, Kelly L., additional, Nicholson, Garth A., additional, Blair, Ian P., additional, Leblond-Manry, Claire, additional, Rouleau, Guy A., additional, Hardiman, Orla, additional, Morrison, Karen E., additional, Veldink, Jan H., additional, van den Berg, Leonard H., additional, Al-Chalabi, Ammar, additional, Pall, Hardev, additional, Shaw, Pamela J., additional, Turner, Martin R., additional, Talbot, Kevin, additional, Taroni, Franco, additional, García-Redondo, Alberto, additional, Wu, Zheyang, additional, Gellera, Cinzia, additional, Ratti, Antonia, additional, Brown, Robert H., additional, Shaw, Christopher E., additional, Ambrose, John C., additional, Arumugam, Prabhu, additional, Baple, Emma L., additional, Bleda, Marta, additional, Boardman-Pretty, Freya, additional, Boissiere, Jeanne M., additional, Boustred, Christopher R., additional, Brittain, H., additional, Caulfield, Mark J., additional, Chan, Georgia C., additional, Craig, Clare E.H., additional, Daugherty, Louise C., additional, de Burca, Anna, additional, Devereau, Andrew, additional, Elgar, Greg, additional, Foulger, Rebecca E., additional, Fowler, Tom, additional, Furió-Tarí, Pedro, additional, Hackett, Joanne M., additional, Halai, Dina, additional, Hamblin, Angela, additional, Henderson, Shirley, additional, Holman, James E., additional, Hubbard, Tim J.P., additional, Jackson, Rob, additional, Jones, Louise J., additional, Kasperaviciute, Dalia, additional, Kayikci, Melis, additional, Lahnstein, Lea, additional, Lawson, Kay, additional, Leigh, Sarah E.A., additional, Leong, Ivonne U.S., additional, Lopez, Javier F., additional, Maleady-Crowe, Fiona, additional, Mason, Joanne, additional, McDonagh, Ellen M., additional, Moutsianas, Loukas, additional, Mueller, Michael, additional, Murugaesu, Nirupa, additional, Need, Anna C., additional, Odhams, Chris A., additional, Patch, Christine, additional, Perez-Gil, Daniel, additional, Polychronopoulos, Dimitris, additional, Pullinger, John, additional, Rahim, Tahrima, additional, Rendon, Augusto, additional, Riesgo-Ferreiro, Pablo, additional, Rogers, Tim, additional, Savage, Kevin, additional, Sawant, Kushmita, additional, Scott, Richard H., additional, Siddiq, Afshan, additional, Sieghart, Alexander, additional, Smedley, Damian, additional, Smith, Katherine R., additional, Sosinsky, Alona, additional, Spooner, William, additional, Stevens, Helen E., additional, Stuckey, Alexander, additional, Sultana, Razvan, additional, Thomas, Ellen R.A., additional, Thompson, Simon R., additional, Tregidgo, Carolyn, additional, Walsh, Emma, additional, Watters, Sarah A., additional, Welland, Matthew J., additional, Williams, Eleanor, additional, Witkowska, Katarzyna, additional, Wood, Suzanne M., additional, Zarowiecki, Magdalena, additional, Arepalli, Sampath, additional, Auluck, Pavan, additional, Baloh, Robert H., additional, Bowser, Robert, additional, Brice, Alexis, additional, Broach, James, additional, Camu, William, additional, Cooper-Knock, John, additional, Corcia, Philippe, additional, Drepper, Carsten, additional, Drory, Vivian E., additional, Dunckley, Travis L., additional, Faghri, Faraz, additional, Farren, Jennifer, additional, Feldman, Eva, additional, Floeter, Mary Kay, additional, Fratta, Pietro, additional, Gerhard, Glenn, additional, Gibson, Summer B., additional, Goutman, Stephen A., additional, Heiman-Patterson, Terry D., additional, Hernandez, Dena G., additional, Hoover, Ben, additional, Jansson, Lilja, additional, Kamel, Freya, additional, Kirby, Janine, additional, Kowall, Neil W., additional, Laaksovirta, Hannu, additional, Landi, Francesco, additional, Le Ber, Isabelle, additional, Lumbroso, Serge, additional, MacGowan, Daniel JL., additional, Maragakis, Nicholas J., additional, Mora, Gabriele, additional, Mouzat, Kevin, additional, Myllykangas, Liisa, additional, Nalls, Mike A., additional, Orrell, Richard W., additional, Ostrow, Lyle W., additional, Pamphlett, Roger, additional, Pioro, Erik, additional, Pulst, Stefan M., additional, Ravits, John M., additional, Renton, Alan E., additional, Robberecht, Wim, additional, Robey, Ian, additional, Rogaeva, Ekaterina, additional, Rothstein, Jeffrey D., additional, Sendtner, Michael, additional, Sidle, Katie C., additional, Simmons, Zachary, additional, Stone, David J., additional, Tienari, Pentti J., additional, Trojanowski, John Q., additional, Troncoso, Juan C., additional, Valori, Miko, additional, Van Damme, Philip, additional, Van Den Bosch, Ludo, additional, Zinman, Lorne, additional, Albani, Diego, additional, Borroni, Barbara, additional, Padovani, Alessandro, additional, Bruni, Amalia, additional, Clarimon, Jordi, additional, Dols-Icardo, Oriol, additional, Illán-Gala, Ignacio, additional, Lleó, Alberto, additional, Danek, Adrian, additional, Galimberti, Daniela, additional, Scarpini, Elio, additional, Serpente, Maria, additional, Graff, Caroline, additional, Chiang, Huei-Hsin, additional, Khoshnood, Behzad, additional, Öijerstedt, Linn, additional, Morris, Christopher M., additional, Nacmias, Benedetta, additional, Sorbi, Sandro, additional, Nielsen, Jorgen E., additional, Hjermind, Lynne E., additional, Novelli, Valeria, additional, Puca, Annibale A., additional, Pastor, Pau, additional, Alvarez, Ignacio, additional, Diez-Fairen, Monica, additional, Aguilar, Miquel, additional, Perneczky, Robert, additional, Diehl-Schimd, Janine, additional, Rossi, Mina, additional, Ruiz, Agustin, additional, Boada, Mercè, additional, Hernández, Isabel, additional, Moreno-Grau, Sonia, additional, Schlachetzki, Johannes C., additional, Aarsland, Dag, additional, Albert, Marilyn S., additional, Attems, Johannes, additional, Barrett, Matthew J., additional, Beach, Thomas G., additional, Bekris, Lynn M., additional, Bennett, David A., additional, Besser, Lilah M., additional, Bigio, Eileen H., additional, Black, Sandra E., additional, Boeve, Bradley F., additional, Bohannan, Ryan C., additional, Brett, Francesca, additional, Brunetti, Maura, additional, Caraway, Chad A., additional, Palma, Jose-Alberto, additional, Calvo, Andrea, additional, Canosa, Antonio, additional, Dickson, Dennis, additional, Duyckaerts, Charles, additional, Faber, Kelley, additional, Ferman, Tanis, additional, Flanagan, Margaret E., additional, Floris, Gianluca, additional, Foroud, Tatiana M., additional, Fortea, Juan, additional, Gan-Or, Ziv, additional, Gentleman, Steve, additional, Ghetti, Bernardino, additional, Gibbs, Jesse Raphael, additional, Goate, Alison, additional, Goldstein, David, additional, González-Aramburu, Isabel, additional, Graff-Radford, Neill R., additional, Hodges, Angela K., additional, Hu, Heng-Chen, additional, Hupalo, Daniel, additional, Infante, Jon, additional, Iranzo, Alex, additional, Kaiser, Scott M., additional, Kaufmann, Horacio, additional, Keith, Julia, additional, Kim, Ronald C., additional, Klein, Gregory, additional, Krüger, Rejko, additional, Kukull, Walter, additional, Kuzma, Amanda, additional, Lage, Carmen, additional, Lesage, Suzanne, additional, Leverenz, James B., additional, Logroscino, Giancarlo, additional, Lopez, Grisel, additional, Love, Seth, additional, Mao, Qinwen, additional, Marti, Maria Jose, additional, Martinez-McGrath, Elisa, additional, Masellis, Mario, additional, Masliah, Eliezer, additional, May, Patrick, additional, McKeith, Ian, additional, Mesulam, Marek-Marsel, additional, Monuki, Edwin S., additional, Newell, Kathy L., additional, Norcliffe-Kaufmann, Lucy, additional, Palmer, Laura, additional, Perkins, Matthew, additional, Pletnikova, Olga, additional, Molina-Porcel, Laura, additional, Reynolds, Regina H., additional, Rodríguez-Rodríguez, Eloy, additional, Rohrer, Jonathan D., additional, Sanchez-Juan, Pascual, additional, Scherzer, Clemens R., additional, Serrano, Geidy E., additional, Shakkottai, Vikram, additional, Sidransky, Ellen, additional, Tayebi, Nahid, additional, Thomas, Alan J., additional, Tilley, Bension S., additional, Walton, Ronald L., additional, Woltjer, Randy, additional, Wszolek, Zbigniew K., additional, Xiromerisiou, Georgia, additional, Zecca, Chiara, additional, Phatnani, Hemali, additional, Kwan, Justin, additional, Sareen, Dhruv, additional, Broach, James R., additional, Arcila-Londono, Ximena, additional, Lee, Edward B., additional, Shneider, Neil A., additional, Fraenkel, Ernest, additional, Zaitlen, Noah, additional, Berry, James D., additional, Malaspina, Andrea, additional, Cox, Gregory A., additional, Thompson, Leslie M., additional, Finkbeiner, Steve, additional, Dardiotis, Efthimios, additional, Miller, Timothy M., additional, Chandran, Siddharthan, additional, Pal, Suvankar, additional, Hornstein, Eran, additional, MacGowan, Daniel J., additional, Heiman-Patterson, Terry, additional, Hammell, Molly G., additional, Patsopoulos, Nikolaos.A., additional, Butovsky, Oleg, additional, Dubnau, Joshua, additional, Nath, Avindra, additional, Harms, Matt, additional, Aronica, Eleonora, additional, Poss, Mary, additional, Phillips-Cremins, Jennifer, additional, Crary, John, additional, Atassi, Nazem, additional, Lange, Dale J., additional, Adams, Darius J., additional, Stefanis, Leonidas, additional, Gotkine, Marc, additional, Babu, Suma, additional, Raj, Towfique, additional, Paganoni, Sabrina, additional, Shalem, Ophir, additional, Smith, Colin, additional, Zhang, Bin, additional, Harris, Brent, additional, Broce, Iris, additional, Drory, Vivian, additional, Ravits, John, additional, McMillan, Corey, additional, Menon, Vilas, additional, Wu, Lani, additional, Altschuler, Steven, additional, Amar, Khaled, additional, Archibald, Neil, additional, Bandmann, Oliver, additional, Capps, Erica, additional, Church, Alistair, additional, Coebergh, Jan, additional, Costantini, Alyssa, additional, Critchley, Peter, additional, Ghosh, Boyd CP., additional, Hu, Michele T.M., additional, Kobylecki, Christopher, additional, Leigh, P. Nigel, additional, Mann, Carl, additional, Massey, Luke A., additional, Nath, Uma, additional, Pavese, Nicola, additional, Paviour, Dominic, additional, Sharma, Jagdish, additional, and Vaughan, Jenny, additional

Published
2021
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11. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Author

Davison, Lucy J., Wallace, Chris, Cooper, Jason D., Cope, Nathan F., Wilson, Nicola K., Smyth, Deborah J., Howson, Joanna M.M., Saleh, Nada, Al-Jeffery, Abdullah, Angus, Karen L., Stevens, Helen E., Nutland, Sarah, Duley, Simon, Coulson, Richard M.R., Walker, Neil M., Burren, Oliver S., Rice, Catherine M., Cambien, Francois, Zeller, Tanja, Munzel, Thomas, Lackner, Karl, Blankenberg, Stefan, Fraser, Peter, Gottgens, Berthold, and Todd, John A.

Published
2012
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13. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Nicol Ferrier, I., Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A, Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Mark Lathrop, G., Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, Paul B., Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., and Donnelly, Peter

Published
2010
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14. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Author

Todd, John A., Evangelou, Marina, Cutler, Antony J., Pekalski, Marcin L., Walker, Neil M., Stevens, Helen E., Porter, Linsey, Smyth, Deborah J., Rainbow, Daniel B., Ferreira, Ricardo C., Esposito, Laura, Hunter, Kara M. D., Loudon, Kevin, Irons, Kathryn, Yang, Jennie H., Bell, Charles J. M., Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah L., Lu, Jia, Greatorex, Jane, Goodfellow, Ian, Wallace, Chris, Tree, Tim I., Evans, Mark, Mander, Adrian P., Bond, Simon, Wicker, Linda S., and Waldron-Lynch, Frank

Subjects
Immunotherapy -- Analysis -- Health aspects -- Research, Interleukin-2 -- Physiological aspects -- Genetic aspects -- Research, Type 1 diabetes -- Analysis -- Health aspects -- Genetic aspects -- Care and treatment -- Research, T cells -- Analysis -- Health aspects -- Physiological aspects -- Genetic aspects -- Research, Biological sciences
Abstract

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4.sup.+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4.sup.+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3.sup.+ CD4.sup.+ CD25.sup.high CD127.sup.low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 x 10.sup.6 to 1.5 x 10.sup.6 IU/m.sup.2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 x 10.sup.6 IU/m.sup.2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 x 10.sup.6 IU/m.sup.2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 x 10.sup.6 and 0.045 x 10.sup.6 IU/m.sup.2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the [beta] chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735, Author(s): John A. Todd 1,*, Marina Evangelou 2, Antony J. Cutler 1, Marcin L. Pekalski 1, Neil M. Walker 1, Helen E. Stevens 1, Linsey Porter 1, Deborah J. Smyth [...]

Published
2016
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16. Antibodies against insulin measured by electrochemiluminescence predicts insulitis severity and disease onset in non-obese diabetic mice and can distinguish human type 1 diabetes status

Author

Lo Bernice, Swafford Austin DE, Shafer-Weaver Kimberly A, Jerome Lawrence F, Rakhlin Luba, Mathern Douglas R, Callahan Conor A, Jiang Ping, Davison Lucy J, Stevens Helen E, Lucas Carrie L, White Jill, von Borstel Reid, Todd John A, and Lenardo Michael J

Subjects
NOD mice, diabetes, human autoantibodies, insulin, electrochemiluminescence, IAA, IA, ECL, Medicine
Abstract

Abstract Background The detection of insulin autoantibodies (IAA) aids in the prediction of autoimmune diabetes development. However, the long-standing, gold standard 125I-insulin radiobinding assay (RBA) has low reproducibility between laboratories, long sample processing times and requires the use of newly synthesized radiolabeled insulin for each set of assays. Therefore, a rapid, non-radioactive, and reproducible assay is highly desirable. Methods We have developed electrochemiluminescence (ECL)-based assays that fulfill these criteria in the measurement of IAA and anti-insulin antibodies (IA) in non-obese diabetic (NOD) mice and in type 1 diabetic individuals, respectively. Using the murine IAA ECL assay, we examined the correlation between IAA, histopathological insulitis, and blood glucose in a cohort of female NOD mice from 4 up to 36 weeks of age. We developed a human IA ECL assay that we compared to conventional RBA and validated using samples from 34 diabetic and 59 non-diabetic individuals in three independent laboratories. Results Our ECL assays were rapid and sensitive with a broad dynamic range and low background. In the NOD mouse model, IAA levels measured by ECL were positively correlated with insulitis severity, and the values measured at 8-10 weeks of age were predictive of diabetes onset. Using human serum and plasma samples, our IA ECL assay yielded reproducible and accurate results with an average sensitivity of 84% at 95% specificity with no statistically significant difference between laboratories. Conclusions These novel, non-radioactive ECL-based assays should facilitate reliable and fast detection of antibodies to insulin and its precursors sera and plasma in a standardized manner between laboratories in both research and clinical settings. Our next step is to evaluate the human IA assay in the detection of IAA in prediabetic subjects or those at risk of type 1 diabetes and to develop similar assays for other autoantibodies that together are predictive for the diagnosis of this common disorder, in order to improve prediction and facilitate future therapeutic trials.

Published
2011
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17. Evidence of association with type 1 diabetes in the SLC11A1 gene region

Author

Walker Neil M, Stevens Helen E, Nutland Sarah, Howson Joanna MM, Downes Kate, Yang Jennie HM, and Todd John A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Linkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform. Methods Nine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C→T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered P ≤ 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR). Results Using the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 × 10-6). There was also some evidence of association at rs4674297 (P = 1.57 × 10-4). No evidence of disease association was obtained at any of the loci using the family collections (PTDT ≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression. Conclusion We conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in SLC11A1 expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages.

Published
2011
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18. Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2

Author

Pekalski, Marcin L., García, Arcadio Rubio, Ferreira, Ricardo C., Rainbow, Daniel B., Smyth, Deborah J., Mashar, Meghavi, Brady, Jane, Savinykh, Natalia, Dopico, Xaquin Castro, Mahmood, Sumiyya, Duley, Simon, Stevens, Helen E., Walker, Neil M., Cutler, Antony J., Waldron-Lynch, Frank, Dunger, David B., Shannon-Lowe, Claire, Coles, Alasdair J., Jones, Joanne L., Wallace, Chris, Todd, John A., and Wicker, Linda S.

Subjects
Immunology, Autoimmunity, chemical and pharmacologic phenomena, Research Article
Abstract

The maintenance of peripheral naive T lymphocytes in humans is dependent on their homeostatic division, not continuing emigration from the thymus, which undergoes involution with age. However, postthymic maintenance of naive T cells is still poorly understood. Previously we reported that recent thymic emigrants (RTEs) are contained in CD31+CD25− naive T cells as defined by their levels of signal joint T cell receptor rearrangement excision circles (sjTRECs). Here, by differential gene expression analysis followed by protein expression and functional studies, we define that the naive T cells having divided the least since thymic emigration express complement receptors (CR1 and CR2) known to bind complement C3b- and C3d-decorated microbial products and, following activation, produce IL-8 (CXCL8), a major chemoattractant for neutrophils in bacterial defense. We also observed an IL-8–producing memory T cell subpopulation coexpressing CR1 and CR2 and with a gene expression signature resembling that of RTEs. The functions of CR1 and CR2 on T cells remain to be determined, but we note that CR2 is the receptor for Epstein-Barr virus, which is a cause of T cell lymphomas and a candidate environmental factor in autoimmune disease., Complement receptors (CR1 and CR2) and IL-8 production identify T cells that have recently left the thymus.

Published
2017

19. Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial

Author

Cutler, Antony J., primary, Oliveira, Joao, additional, Ferreira, Ricardo C., additional, Challis, Ben, additional, Walker, Neil M., additional, Caddy, Sarah, additional, Lu, Jia, additional, Stevens, Helen E., additional, Smyth, Deborah J., additional, Pekalski, Marcin L., additional, Kennet, Jane, additional, Hunter, Kara M.D., additional, Goodfellow, Ian, additional, Wicker, Linda S., additional, Todd, John A., additional, and Waldron-Lynch, Frank, additional

Published
2017
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20. Recent thymic emigrants produce antimicrobial IL-8, express complement receptors and are precursors of a tissue-homing Th8 lineage of memory cells

Author

Pekalski, Marcin L, primary, García, Arcadio Rubio, additional, Ferreira, Ricardo C, additional, Rainbow, Daniel B, additional, Smyth, Deborah J, additional, Mashar, Meghavi, additional, Brady, Jane, additional, Savinykh, Natalia, additional, Dopico, Xaquin Castro, additional, Mahmood, Sumiyya, additional, Duley, Simon, additional, Stevens, Helen E, additional, Walker, Neil M, additional, Cutler, Antony J, additional, Waldron-Lynch, Frank, additional, Dunger, David B, additional, Shannon-Lowe, Claire, additional, Coles, Alasdair J, additional, Jones, Joanne L, additional, Wallace, Chris, additional, Todd, John A, additional, and Wicker, Linda S, additional

Published
2016
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21. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author

Bodea, Corneliu A., primary, Neale, Benjamin M., additional, Ripke, Stephan, additional, Daly, Mark J., additional, Devlin, Bernie, additional, Roeder, Kathryn, additional, Barclay, Murray, additional, Peyrin-Biroulet, Laurent, additional, Chamaillard, Mathias, additional, Colombel, Jean-Frederick, additional, Cottone, Mario, additional, Croft, Anthony, additional, D’Incà, Renata, additional, Halfvarson, Jonas, additional, Hanigan, Katherine, additional, Henderson, Paul, additional, Hugot, Jean-Pierre, additional, Karban, Amir, additional, Kennedy, Nicholas A., additional, Khan, Mohammed Azam, additional, Lémann, Marc, additional, Levine, Arie, additional, Massey, Dunecan, additional, Milla, Monica, additional, Montgomery, Grant W., additional, Ng, Sok Meng Evelyn, additional, Oikonomou, Ioannis, additional, Peeters, Harald, additional, Proctor, Deborah D., additional, Rahier, Jean-Francois, additional, Roberts, Rebecca, additional, Rutgeerts, Paul, additional, Seibold, Frank, additional, Stronati, Laura, additional, Taylor, Kirstin M., additional, Törkvist, Leif, additional, Ublick, Kullak, additional, Van Limbergen, Johan, additional, Van Gossum, Andre, additional, Vatn, Morten H., additional, Zhang, Hu, additional, Zhang, Wei, additional, Andrews, Jane M., additional, Bampton, Peter A., additional, Florin, Timothy H., additional, Gearry, Richard, additional, Krishnaprasad, Krupa, additional, Lawrance, Ian C., additional, Mahy, Gillian, additional, Radford-Smith, Graham, additional, Roberts, Rebecca L., additional, Simms, Lisa A., additional, Amininijad, Leila, additional, Cleynen, Isabelle, additional, Dewit, Olivier, additional, Franchimont, Denis, additional, Georges, Michel, additional, Laukens, Debby, additional, Theatre, Emilie, additional, Van Gossum, André, additional, Vermeire, Severine, additional, Aumais, Guy, additional, Baidoo, Leonard, additional, Barrie, Arthur M., additional, Beck, Karen, additional, Bernard, Edmond-Jean, additional, Binion, David G., additional, Bitton, Alain, additional, Brant, Steve R., additional, Cho, Judy H., additional, Cohen, Albert, additional, Croitoru, Kenneth, additional, Datta, Lisa W., additional, Deslandres, Colette, additional, Duerr, Richard H., additional, Dutridge, Debra, additional, Ferguson, John, additional, Fultz, Joann, additional, Goyette, Philippe, additional, Greenberg, Gordon R., additional, Haritunians, Talin, additional, Jobin, Gilles, additional, Katz, Seymour, additional, Lahaie, Raymond G., additional, McGovern, Dermot P., additional, Nelson, Linda, additional, Ng, Sok Meng, additional, Ning, Kaida, additional, Paré, Pierre, additional, Regueiro, Miguel D., additional, Rioux, John D., additional, Ruggiero, Elizabeth, additional, Schumm, L. Philip, additional, Schwartz, Marc, additional, Scott, Regan, additional, Sharma, Yashoda, additional, Silverberg, Mark S., additional, Spears, Denise, additional, Steinhart, A. Hillary, additional, Stempak, Joanne M., additional, Swoger, Jason M., additional, Tsagarelis, Constantina, additional, Zhang, Clarence, additional, Zhao, Hongyu, additional, Aerts, Jan, additional, Ahmad, Tariq, additional, Arbury, Hazel, additional, Attwood, Anthony, additional, Auton, Adam, additional, Ball, Stephen G., additional, Balmforth, Anthony J., additional, Barnes, Chris, additional, Barrett, Jeffrey C., additional, Barroso, Inês, additional, Barton, Anne, additional, Bennett, Amanda J., additional, Bhaskar, Sanjeev, additional, Blaszczyk, Katarzyna, additional, Bowes, John, additional, Brand, Oliver J., additional, Braund, Peter S., additional, Bredin, Francesca, additional, Breen, Gerome, additional, Brown, Morris J., additional, Bruce, Ian N., additional, Bull, Jaswinder, additional, Burren, Oliver S., additional, Burton, John, additional, Byrnes, Jake, additional, Caesar, Sian, additional, Cardin, Niall, additional, Clee, Chris M., additional, Coffey, Alison J., additional, Connell, John M.C., additional, Conrad, Donald F., additional, Cooper, Jason D., additional, Dominiczak, Anna F., additional, Downes, Kate, additional, Drummond, Hazel E., additional, Dudakia, Darshna, additional, Dunham, Andrew, additional, Ebbs, Bernadette, additional, Eccles, Diana, additional, Edkins, Sarah, additional, Edwards, Cathryn, additional, Elliot, Anna, additional, Emery, Paul, additional, Evans, David M., additional, Evans, Gareth, additional, Eyre, Steve, additional, Farmer, Anne, additional, Ferrier, Nicol, additional, Flynn, Edward, additional, Forbes, Alistair, additional, Forty, Liz, additional, Franklyn, Jayne A., additional, Frayling, Timothy M., additional, Freathy, Rachel M., additional, Giannoulatou, Eleni, additional, Gibbs, Polly, additional, Gilbert, Paul, additional, Gordon-Smith, Katherine, additional, Gray, Emma, additional, Green, Elaine, additional, Groves, Chris J., additional, Grozeva, Detelina, additional, Gwilliam, Rhian, additional, Hall, Anita, additional, Hammond, Naomi, additional, Hardy, Matt, additional, Harrison, Pile, additional, Hassanali, Neelam, additional, Hebaishi, Husam, additional, Hines, Sarah, additional, Hinks, Anne, additional, Hitman, Graham A., additional, Hocking, Lynne, additional, Holmes, Chris, additional, Howard, Eleanor, additional, Howard, Philip, additional, Howson, Joanna M.M., additional, Hughes, Debbie, additional, Hunt, Sarah, additional, Isaacs, John D., additional, Jain, Mahim, additional, Jewell, Derek P., additional, Johnson, Toby, additional, Jolley, Jennifer D., additional, Jones, Ian R., additional, Jones, Lisa A., additional, Kirov, George, additional, Langford, Cordelia F., additional, Lango-Allen, Hana, additional, Lathrop, G. Mark, additional, Lee, James, additional, Lee, Kate L., additional, Lees, Charlie, additional, Lewis, Kevin, additional, Lindgren, Cecilia M., additional, Maisuria-Armer, Meeta, additional, Maller, Julian, additional, Mansfield, John, additional, Marchini, Jonathan L., additional, Martin, Paul, additional, Massey, Dunecan C.O., additional, McArdle, Wendy L., additional, McGuffin, Peter, additional, McLay, Kirsten E., additional, McVean, Gil, additional, Mentzer, Alex, additional, Mimmack, Michael L., additional, Morgan, Ann E., additional, Morris, Andrew P., additional, Mowat, Craig, additional, Munroe, Patricia B., additional, Myers, Simon, additional, Newman, William, additional, Nimmo, Elaine R., additional, O’Donovan, Michael C., additional, Onipinla, Abiodun, additional, Ovington, Nigel R., additional, Owen, Michael J., additional, Palin, Kimmo, additional, Palotie, Aarno, additional, Parnell, Kirstie, additional, Pearson, Richard, additional, Pernet, David, additional, Perry, John R.B., additional, Phillips, Anne, additional, Plagnol, Vincent, additional, Prescott, Natalie J., additional, Prokopenko, Inga, additional, Quail, Michael A., additional, Rafelt, Suzanne, additional, Rayner, Nigel W., additional, Reid, David M., additional, Renwick, Anthony, additional, Ring, Susan M., additional, Robertson, Neil, additional, Robson, Samuel, additional, Russell, Ellie, additional, St Clair, David, additional, Sambrook, Jennifer G., additional, Sanderson, Jeremy D., additional, Sawcer, Stephen J., additional, Schuilenburg, Helen, additional, Scott, Carol E., additional, Scott, Richard, additional, Seal, Sheila, additional, Shaw-Hawkins, Sue, additional, Shields, Beverley M., additional, Simmonds, Matthew J., additional, Smyth, Debbie J., additional, Somaskantharajah, Elilan, additional, Spanova, Katarina, additional, Steer, Sophia, additional, Stephens, Jonathan, additional, Stevens, Helen E., additional, Stirrups, Kathy, additional, Stone, Millicent A., additional, Strachan, David P., additional, Su, Zhan, additional, Symmons, Deborah P.M., additional, Thompson, John R., additional, Thomson, Wendy, additional, Tobin, Martin D., additional, Travers, Mary E., additional, Turnbull, Clare, additional, Vukcevic, Damjan, additional, Wain, Louise V., additional, Walker, Mark, additional, Walker, Neil M., additional, Wallace, Chris, additional, Warren-Perry, Margaret, additional, Watkins, Nicholas A., additional, Webster, John, additional, Weedon, Michael N., additional, Wilson, Anthony G., additional, Woodburn, Matthew, additional, Wordsworth, B. Paul, additional, Yau, Chris, additional, Young, Allan H., additional, Zeggini, Eleftheria, additional, Brown, Matthew A., additional, Burton, Paul R., additional, Caulfield, Mark J., additional, Compston, Alastair, additional, Farrall, Martin, additional, Gough, Stephen C.L., additional, Hall, Alistair S., additional, Hattersley, Andrew T., additional, Hill, Adrian V.S., additional, Mathew, Christopher G., additional, Pembrey, Marcus, additional, Satsangi, Jack, additional, Stratton, Michael R., additional, Worthington, Jane, additional, Hurles, Matthew E., additional, Duncanson, Audrey, additional, Ouwehand, Willem H., additional, Parkes, Miles, additional, Rahman, Nazneen, additional, Todd, John A., additional, Samani, Nilesh J., additional, Kwiatkowski, Dominic P., additional, McCarthy, Mark I., additional, Craddock, Nick, additional, Deloukas, Panos, additional, Donnelly, Peter, additional, Blackwell, Jenefer M., additional, Bramon, Elvira, additional, Casas, Juan P., additional, Corvin, Aiden, additional, Jankowski, Janusz, additional, Markus, Hugh S., additional, Palmer, Colin N.A., additional, Plomin, Robert, additional, Rautanen, Anna, additional, Trembath, Richard C., additional, Viswanathan, Ananth C., additional, Wood, Nicholas W., additional, Spencer, Chris C.A., additional, Band, Gavin, additional, Bellenguez, Céline, additional, Freeman, Colin, additional, Hellenthal, Garrett, additional, Pirinen, Matti, additional, Strange, Amy, additional, Blackburn, Hannah, additional, Bumpstead, Suzannah J., additional, Dronov, Serge, additional, Gillman, Matthew, additional, Jayakumar, Alagurevathi, additional, McCann, Owen T., additional, Liddle, Jennifer, additional, Potter, Simon C., additional, Ravindrarajah, Radhi, additional, Ricketts, Michelle, additional, Waller, Matthew, additional, Weston, Paul, additional, Widaa, Sara, additional, and Whittaker, Pamela, additional

Published
2016
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22. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Author

Davison, Lucy J, Wallace, Chris, Cooper, Jason D, Cope, Nathan F, Wilson, Nicola K, Smyth, Deborah J, Howson, Joanna M M, Saleh, Nada, Al-Jeffery, Abdullah, Angus, Karen L, Stevens, Helen E, Nutland, Sarah, Duley, Simon, Coulson, Richard M R, Walker, Neil M, Burren, Oliver S, Rice, Catherine M, Cambien, Francois, Zeller, Tanja, Munzel, Thomas, Lackner, Karl, Blankenberg, Stefan, Fraser, Peter, Gottgens, Berthold, Todd, John A, Davison, Lucy J, Wallace, Chris, Cooper, Jason D, Cope, Nathan F, Wilson, Nicola K, Smyth, Deborah J, Howson, Joanna M M, Saleh, Nada, Al-Jeffery, Abdullah, Angus, Karen L, Stevens, Helen E, Nutland, Sarah, Duley, Simon, Coulson, Richard M R, Walker, Neil M, Burren, Oliver S, Rice, Catherine M, Cambien, Francois, Zeller, Tanja, Munzel, Thomas, Lackner, Karl, Blankenberg, Stefan, Fraser, Peter, Gottgens, Berthold, and Todd, John A

Abstract

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes., Per Lundmark and Ann-Christine Syvänen (Institution for Medical Sciences, Uppsala University, Uppsala, Sweden) contributed to this study.

Published
2012
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23. Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

Author

Downes, Kate, primary, Marcovecchio, M. Loredana, additional, Clarke, Pamela, additional, Cooper, Jason D., additional, Ferreira, Ricardo C., additional, Howson, Joanna M. M., additional, Jolley, Jennifer, additional, Nutland, Sarah, additional, Stevens, Helen E., additional, Walker, Neil M., additional, Wallace, Chris, additional, Dunger, David B., additional, and Todd, John A., additional

Published
2013
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24. Postthymic Expansion in Human CD4 Naive T Cells Defined by Expression of Functional High-Affinity IL-2 Receptors

Author

Pekalski, Marcin L., primary, Ferreira, Ricardo C., additional, Coulson, Richard M. R., additional, Cutler, Antony J., additional, Guo, Hui, additional, Smyth, Deborah J., additional, Downes, Kate, additional, Dendrou, Calliope A., additional, Castro Dopico, Xaquin, additional, Esposito, Laura, additional, Coleman, Gillian, additional, Stevens, Helen E., additional, Nutland, Sarah, additional, Walker, Neil M., additional, Guy, Catherine, additional, Dunger, David B., additional, Wallace, Chris, additional, Tree, Timothy I. M., additional, Todd, John A., additional, and Wicker, Linda S., additional

Published
2013
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25. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Author

Davison, Lucy J., primary, Wallace, Chris, additional, Cooper, Jason D., additional, Cope, Nathan F., additional, Wilson, Nicola K., additional, Smyth, Deborah J., additional, Howson, Joanna M.M., additional, Saleh, Nada, additional, Al-Jeffery, Abdullah, additional, Angus, Karen L., additional, Stevens, Helen E., additional, Nutland, Sarah, additional, Duley, Simon, additional, Coulson, Richard M.R., additional, Walker, Neil M., additional, Burren, Oliver S., additional, Rice, Catherine M., additional, Cambien, Francois, additional, Zeller, Tanja, additional, Munzel, Thomas, additional, Lackner, Karl, additional, Blankenberg, Stefan, additional, Fraser, Peter, additional, Gottgens, Berthold, additional, and Todd, John A., additional

Published
2011
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27. Common Genetic Determinants of Vitamin D Insufficiency: A Genome-Wide Association Study

Author

Wang, Thomas J., primary, Zhang, Feng, additional, Richards, J. Brent, additional, Kestenbaum, Bryan, additional, van Meurs, Joyce B., additional, Berry, Diane, additional, Kiel, Douglas P., additional, Streeten, Elizabeth A., additional, Ohlsson, Claes, additional, Koller, Daniel L., additional, Peltonen, Leena, additional, Cooper, Jason D., additional, O'Reilly, Paul F., additional, Houston, Denise K., additional, Glazer, Nicole L., additional, Vandenput, Liesbeth, additional, Peacock, Munro, additional, Shi, Julia, additional, Rivadeneira, Fernando, additional, McCarthy, Mark I., additional, Anneli, Pouta, additional, de Boer, Ian H., additional, Mangino, Massimo, additional, Kato, Bernet, additional, Smyth, Deborah J., additional, Booth, Sarah L., additional, Jacques, Paul F., additional, Burke, Greg L., additional, Goodarzi, Mark, additional, Cheung, Ching-Lung, additional, Wolf, Myles, additional, Rice, Kenneth, additional, Goltzman, David, additional, Hidiroglou, Nick, additional, Ladouceur, Martin, additional, Wareham, Nicholas J., additional, Hocking, Lynne J., additional, Hart, Deborah, additional, Arden, Nigel K., additional, Cooper, Cyrus, additional, Malik, Suneil, additional, Fraser, William D., additional, Hartikainen, Anna-Liisa, additional, Zhai, Guangju, additional, Macdonald, Helen M., additional, Forouhi, Nita G., additional, Loos, Ruth J. F., additional, Reid, David M., additional, Hakim, Alan, additional, Dennison, Elaine, additional, Liu, Yongmei, additional, Power, Chris, additional, Stevens, Helen E., additional, Jaana, Laitinen, additional, Vasan, Ramachandran S., additional, Soranzo, Nicole, additional, Bojunga, Jörg, additional, Psaty, Bruce M., additional, Lorentzon, Mattias, additional, Foroud, Tatiana, additional, Harris, Tamara B., additional, Hofman, Albert, additional, Jansson, John-Olov, additional, Cauley, Jane A., additional, Uitterlinden, Andre G., additional, Gibson, Quince, additional, Järvelin, Marjo-Riitta, additional, Karasik, David, additional, Siscovick, David S., additional, Econs, Michael J., additional, Kritchevsky, Stephen B., additional, Florez, Jose C., additional, Todd, John A., additional, Dupuis, Josee, additional, Hyppönen, Elina, additional, and Spector, Timothy D., additional

Published
2011
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29. Population structure, differential bias and genomic control in a large-scale, case-control association study

Author

Clayton, David G, primary, Walker, Neil M, additional, Smyth, Deborah J, additional, Pask, Rebecca, additional, Cooper, Jason D, additional, Maier, Lisa M, additional, Smink, Luc J, additional, Lam, Alex C, additional, Ovington, Nigel R, additional, Stevens, Helen E, additional, Nutland, Sarah, additional, Howson, Joanna M M, additional, Faham, Malek, additional, Moorhead, Martin, additional, Jones, Hywel B, additional, Falkowski, Matthew, additional, Hardenbol, Paul, additional, Willis, Thomas D, additional, and Todd, John A, additional

Published
2005
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30. Evaluation of Single Nucleotide Polymorphism Typing with Invader on PCR Amplicons and Its Automation

Author

Mein, Charles A., primary, Barratt, Bryan J., additional, Dunn, Michael G., additional, Siegmund, Thorsten, additional, Smith, Annabel N., additional, Esposito, Laura, additional, Nutland, Sarah, additional, Stevens, Helen E., additional, Wilson, Amanda J., additional, Phillips, Michael S., additional, Jarvis, Nancy, additional, Law, Scott, additional, de Arruda, Monika, additional, and Todd, John A., additional

Published
2000
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31. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.

Author

Todd, John A., Walker, Neil M., Cooper, Jason D., Smyth, Deborah J., Downes, Kate, Plagnol, Vincent, Bailey, Rebecca, Nejentsev, Sergey, Field, Sarah F., Payne, Felicity, Lowe, Christopher E., Szeszko, Jeffrey S., Hafler, Jason P., Zeitels, Lauren, Yang, Jennie H. M., Vella, Adrian, Nutland, Sarah, Stevens, Helen E., Schuilenburg, Helen, and Coleman, Gillian

Subjects
GENOMICS, DIABETES, AUTOIMMUNE diseases, GENETIC polymorphisms, GENETICS of disease susceptibility, THYROID diseases, GRAVES' disease
Abstract

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 × 10−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (Pfollow-up ≤ 1.35 × 10−9; Poverall ≤ 1.15 × 10−14), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (Poverall = 1.38 × 10−8) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten. [ABSTRACT FROM AUTHOR]

Published
2007
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32. Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

Author

Downes, Kate, Marcovecchio, M Loredana, Clarke, Pamela, Cooper, Jason D, Ferreira, Ricardo C, Howson, Joanna MM, Jolley, Jennifer, Nutland, Sarah, Stevens, Helen E, Walker, Neil M, Wallace, Chris, Dunger, David B, Todd, John A, Downes, Kate [0000-0003-0366-1579], Marcovecchio, Loredana [0000-0002-4415-316X], Howson, Joanna [0000-0001-7618-0050], Wallace, Chris [0000-0001-9755-1703], Dunger, David [0000-0002-2566-9304], and Apollo - University of Cambridge Repository

Subjects
Adult, Immunoassay, Inflammation, Male, Adolescent, C-Peptide, Endocrinology, Diabetes and Metabolism, Interleukin-2 Receptor alpha Subunit, Middle Aged, Diabetes Mellitus, Type 1, Case-Control Studies, Insulin-Secreting Cells, Disease Progression, Internal Medicine, Humans, Female, Biomarkers, Aged
Abstract

AIMS/HYPOTHESIS: Type 1 diabetes is a common autoimmune disease that has genetic and environmental determinants. Variations within the IL2 and IL2RA (also known as CD25) gene regions are associated with disease risk, and variation in expression or function of these proteins is likely to be causal. We aimed to investigate if circulating concentrations of the soluble form of CD25, sCD25, an established marker of immune activation and inflammation, were increased in individuals with type 1 diabetes and if this was associated with the concentration of C-peptide, a measure of insulin production that reflects the degree of autoimmune destruction of the insulin-producing beta cells. METHODS: We used immunoassays to measure sCD25 and C-peptide in peripheral blood plasma from patient and control samples. RESULTS: We identified that sCD25 was increased in patients with type 1 diabetes compared with controls and replicated this result in an independent set of 86 adult patient and 80 age-matched control samples (p = 1.17 × 10(-3)). In 230 patients under 20 years of age, with median duration-of-disease of 6.1 years, concentrations of sCD25 were negatively associated with C-peptide concentrations (p = 4.8 × 10(-3)). CONCLUSIONS/INTERPRETATION: The 25% increase in sCD25 in patients, alongside the inverse association between sCD25 and C-peptide, probably reflect the adverse effects of an on-going, actively autoimmune and inflammatory immune system on beta cell function in patients.

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33. Interaction analysis of the CBLBand CTLA4genes in type 1 diabetes

Author

Payne, Felicity, Cooper, Jason D., Walker, Neil M., Lam, Alex C., Smink, Luc J., Nutland, Sarah, Stevens, Helen E., Hutchings, Jayne, and Todd, John A.

Abstract

Gene‐gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of a statistical interaction between polymorphisms in two negative immunoregulatory genes, CBLBand CTLA4, has been reported in type 1 diabetes (T1D). This study, in 480 Danish families, reported an association between T1D and a synonymous coding SNP in exon 12 of the CBLBgene (rs3772534 G>A; minor allele frequency, MAF=0.24; derived relative risk, RR for G allele=1.78; P=0.046). Furthermore, evidence of a statistical interaction with the known T1D susceptibility‐associated CTLA4polymorphism rs3087243 (laboratory name CT60, G>A) was reported (P<0.0001), such that the CBLBSNP rs3772534 G allele was overtransmitted to offspring with the CTLA4rs3087243 G/G genotype. We have, therefore, attempted to obtain additional support for this finding in both large family and case‐control collections. In a primary analysis, no evidence for an association of the CBLBSNP rs3772534 with disease was found in either sample set (2162 parent‐child trios, P=0.33; 3453 cases and 3655 controls, P=0.69). In the case‐only statistical interaction analysis between rs3772534 and rs3087243, there was also no support for an effect (1994 T1D affected offspring, and 3215 cases, P=0.92). These data highlight the need for large, well‐characterized populations, offering the possibility of obtaining additional support for initial observations owing to the low prior probability of identifying reproducible evidence of gene‐gene interactions in the analysis of common disease‐associated variants in human populations.

Published
2007
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34. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Author

Romagnoni, Alberto, Jégou, Simon, Van Steen, Kristel, Wainrib, Gilles, Hugot, Jean-Pierre, Peyrin-Biroulet, Laurent, Chamaillard, Mathias, Colombel, Jean-Frederick, Cottone, Mario, D’Amato, Mauro, D’Incà, Renata, Halfvarson, Jonas, Henderson, Paul, Karban, Amir, Kennedy, Nicholas A., Khan, Mohammed Azam, Lémann, Marc, Levine, Arie, Massey, Dunecan, Milla, Monica, Ng, Sok Meng Evelyn, Oikonomou, Ioannis, Peeters, Harald, Proctor, Deborah D., Rahier, Jean-Francois, Rutgeerts, Paul, Seibold, Frank, Stronati, Laura, Taylor, Kirstin M., Törkvist, Leif, Ublick, Kullak, Van Limbergen, Johan, Van Gossum, Andre, Vatn, Morten H., Zhang, Hu, Zhang, Wei, Andrews, Jane M., Bampton, Peter A., Barclay, Murray, Florin, Timothy H., Gearry, Richard, Krishnaprasad, Krupa, Lawrance, Ian C., Mahy, Gillian, Montgomery, Grant W., Radford-Smith, Graham, Roberts, Rebecca L., Simms, Lisa A., Hanigan, Katherine, Croft, Anthony, Amininijad, Leila, Cleynen, Isabelle, Dewit, Olivier, Franchimont, Denis, Georges, Michel, Laukens, Debby, Theatre, Emilie, Van Gossum, André, Vermeire, Severine, Aumais, Guy, Baidoo, Leonard, Barrie, Arthur M., Beck, Karen, Bernard, Edmond-Jean, Binion, David G., Bitton, Alain, Brant, Steve R., Cho, Judy H., Cohen, Albert, Croitoru, Kenneth, Daly, Mark J., Datta, Lisa W., Deslandres, Colette, Duerr, Richard H., Dutridge, Debra, Ferguson, John, Fultz, Joann, Goyette, Philippe, Greenberg, Gordon R., Haritunians, Talin, Jobin, Gilles, Katz, Seymour, Lahaie, Raymond G., McGovern, Dermot P., Nelson, Linda, Ng, Sok Meng, Ning, Kaida, Paré, Pierre, Regueiro, Miguel D., Rioux, John D., Ruggiero, Elizabeth, Schumm, L. Philip, Schwartz, Marc, Scott, Regan, Sharma, Yashoda, Silverberg, Mark S., Spears, Denise, Steinhart, A. Hillary, Stempak, Joanne M., Swoger, Jason M., Tsagarelis, Constantina, Zhang, Clarence, Zhao, Hongyu, Aerts, Jan, Ahmad, Tariq, Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barnes, Chris, Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Cardin, Niall, Clee, Chris M., Coffey, Alison J., MC Connell, John, Conrad, Donald F., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Ferrier, I. Nicol, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Frayling, Timothy M., Freathy, Rachel M., Giannoulatou, Eleni, Gibbs, Polly, Gilbert, Paul, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A., Hocking, Lynne, Holmes, Chris, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Lathrop, G. Mark, Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Marchini, Jonathan L., Martin, Paul, Massey, Dunecan CO, McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., McVean, Gil, Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Munroe, Patricia B., Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Palotie, Aarno, Parnell, Kirstie, Pearson, Richard, Pernet, David, Perry, John RB, Phillips, Anne, Plagnol, Vincent, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Robson, Samuel, Russell, Ellie, Clair, David St, Sambrook, Jennifer G., Sanderson, Jeremy D., Sawcer, Stephen J., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stirrups, Kathy, Stone, Millicent A., Strachan, David P., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Tobin, Martin D., Travers, Mary E., Turnbull, Clare, Vukcevic, Damjan, Wain, Louise V., Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Yau, Chris, Young, Allan H., Zeggini, Eleftheria, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Hurles, Matthew E., Duncanson, Audrey, Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., Kwiatkowski, Dominic P., McCarthy, Mark I., Craddock, Nick, Deloukas, Panos, Donnelly, Peter, Blackwell, Jenefer M., Bramon, Elvira, Casas, Juan P., Corvin, Aiden, Jankowski, Janusz, Markus, Hugh S., Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C. A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Pirinen, Matti, Strange, Amy, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
692/4020/1503/257/1402, 45, 692/308/2056, 45/43, article, 129, 3. Good health
Abstract

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

35. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Author

Todd, John A, Evangelou, Marina, Cutler, Antony J, Pekalski, Marcin L, Walker, Neil M, Stevens, Helen E, Porter, Linsey, Smyth, Deborah J, Rainbow, Daniel B, Ferreira, Ricardo C, Esposito, Laura, Hunter, Kara MD, Loudon, Kevin, Irons, Kathryn, Yang, Jennie H, Bell, Charles JM, Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah L, Lu, Jia, Greatorex, Jane, Goodfellow, Ian, Wallace, Chris, Tree, Tim I, Evans, Mark, Mander, Adrian P, Bond, Simon, Wicker, Linda S, and Waldron-Lynch, Frank

Subjects
Adult, Male, Adolescent, Dose-Response Relationship, Drug, Middle Aged, T-Lymphocytes, Regulatory, Recombinant Proteins, 3. Good health, Immunophenotyping, Eosinophils, Killer Cells, Natural, Young Adult, Diabetes Mellitus, Type 1, Humans, Interleukin-2, Female, Lymphocyte Count, Chemokines, Inflammation Mediators, Biomarkers
Abstract

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

36. Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial

Author

Cutler, Antony J, Oliveira, Joao, Ferreira, Ricardo C, Challis, Ben, Walker, Neil M, Caddy, Sarah, Lu, Jia, Stevens, Helen E, Smyth, Deborah J, Pekalski, Marcin L, Kennet, Jane, Hunter, Kara MD, Goodfellow, Ian, Wicker, Linda S, Todd, John A, and Waldron-Lynch, Frank

Subjects
T regulatory cells, Interleukin-2, norovirus, hemic and immune systems, chemical and pharmacologic phenomena, Proleukin, clinical trial, aldesleukin, immune response, 3. Good health
Abstract

BACKGROUND: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. METHODS: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. RESULTS: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4 + T cell (Treg), effector T cell (Teff) CD4 + and CD8 + subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69 + and Ki-67 + effector memory Teffs were followed by the emergence of memory CD8 + Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. CONCLUSIONS: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.

37. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

Author

Todd, John A, Evangelou, Marina, Cutler, Antony J, Pekalski, Marcin L, Walker, Neil M, Stevens, Helen E, Porter, Linsey, Smyth, Deborah J, Rainbow, Daniel B, Ferreira, Ricardo C, Esposito, Laura, Hunter, Kara MD, Loudon, Kevin, Irons, Kathryn, Yang, Jennie H, Bell, Charles JM, Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah, Lu, Jia, Greatorex, Jane, Goodfellow, Ian Gordon, Wallace, Chris, Tree, Tim I, Evans, Mark, Mander, Adrian Paul, Bond, Simon, Wicker, Linda S, and Waldron-Lynch, Frank

Subjects
lymphocytes, blood counts, blood, memory T cells, T cells, eosinophils, regulatory T cells, 3. Good health, blood plasma
Abstract

BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735., This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.1002139

38. Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

Author

Downes, Kate, Marcovecchio, M Loredana, Clarke, Pamela, Cooper, Jason D, Ferreira, Ricardo C, Howson, Joanna MM, Jolley, Jennifer, Nutland, Sarah, Stevens, Helen E, Walker, Neil M, Wallace, Chris, Dunger, David B, and Todd, John A

Subjects
Adult, Immunoassay, Inflammation, Male, Adolescent, C-Peptide, Interleukin-2 Receptor alpha Subunit, Middle Aged, 3. Good health, Diabetes Mellitus, Type 1, Case-Control Studies, Insulin-Secreting Cells, Disease Progression, Humans, Female, Biomarkers, Aged
Abstract

AIMS/HYPOTHESIS: Type 1 diabetes is a common autoimmune disease that has genetic and environmental determinants. Variations within the IL2 and IL2RA (also known as CD25) gene regions are associated with disease risk, and variation in expression or function of these proteins is likely to be causal. We aimed to investigate if circulating concentrations of the soluble form of CD25, sCD25, an established marker of immune activation and inflammation, were increased in individuals with type 1 diabetes and if this was associated with the concentration of C-peptide, a measure of insulin production that reflects the degree of autoimmune destruction of the insulin-producing beta cells. METHODS: We used immunoassays to measure sCD25 and C-peptide in peripheral blood plasma from patient and control samples. RESULTS: We identified that sCD25 was increased in patients with type 1 diabetes compared with controls and replicated this result in an independent set of 86 adult patient and 80 age-matched control samples (p = 1.17 × 10(-3)). In 230 patients under 20 years of age, with median duration-of-disease of 6.1 years, concentrations of sCD25 were negatively associated with C-peptide concentrations (p = 4.8 × 10(-3)). CONCLUSIONS/INTERPRETATION: The 25% increase in sCD25 in patients, alongside the inverse association between sCD25 and C-peptide, probably reflect the adverse effects of an on-going, actively autoimmune and inflammatory immune system on beta cell function in patients.

39. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Author

Nejentsev, Sergey, Howson, Joanna M. M., Walker, Neil M., Szeszko, Jeffrey, Field, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., Todd, John A., Burton, Paul R., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Taylor, Niall C., Walters, Graham R., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O’Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Nicol Ferrier, I., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Khalid Mohiuddin, M., Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Braga, Carolina A., Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bryan, Claire, Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Jilur, Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingeleif B., Howie, Bryan N., Su, Zhan, Ying Teo, Yik, Vukcevic, Damjan, Bentley, David, Compston, Alistair, Nejentsev, Sergey, Howson, Joanna M. M., Walker, Neil M., Szeszko, Jeffrey, Field, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., Todd, John A., Burton, Paul R., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Taylor, Niall C., Walters, Graham R., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O’Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Nicol Ferrier, I., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Khalid Mohiuddin, M., Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Braga, Carolina A., Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bryan, Claire, Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Jilur, Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingeleif B., Howie, Bryan N., Su, Zhan, Ying Teo, Yik, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Abstract

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group.

40. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author

Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, and Genomics (BRAGGS), The Biologics in RA Genetics, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Susceptibility Collaboration (UK), Breast Cancer, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, Compston, Alistair, Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, and Genomics (BRAGGS), The Biologics in RA Genetics, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Susceptibility Collaboration (UK), Breast Cancer, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Abstract

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approx2,000 individuals for each of 7 major diseases and a shared set of approx3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 times 10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5 times 10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource

41. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Author

Burton, Paul R, Clayton, David G, Cardon, Lon R, Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P, McCarthy, Mark I, Ouwehand, Willem H, Samani, Nilesh J, Todd, John A, Donnelly (Chair), Peter, Barrett, Jeffrey C, Davison, Dan, Donnelly, Peter, Easton, Doug, Evans, David M, Leung, Hin-Tak, Marchini, Jonathan L, Morris, Andrew P, Spencer, Chris CA, Tobin, Martin D, Attwood, Antony P, Boorman, James P, Cant, Barbara, Everson, Ursula, Hussey, Judith M, Jolley, Jennifer D, Knight, Alexandra S, Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V, Stevens, Helen E, Taylor, Niall C, Walters, Graham R, Walker, Neil M, Watkins, Nicholas A, Winzer, Thilo, Jones, Richard W, McArdle, Wendy L, Ring, Susan M, Strachan, David P, Pembrey, Marcus, Breen, Gerome, Clair, David St, Caesar, Sian, Gordon-Smith, Katharine, Jones, Lisa, Fraser, Christine, Green, Elaine K, Grozeva, Detelina, Hamshere, Marian L, Holmans, Peter A, Jones, Ian R, Kirov, George, Moskivina, Valentina, Nikolov, Ivan, O'Donovan, Michael C, Owen, Michael J, Collier, David A, Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H, Ferrier, I Nicol, Ball, Stephen G, Balmforth, Anthony J, Barrett, Jennifer H, Bishop, Timothy D, Iles, Mark M, Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S, Braund, Peter S, Dixon, Richard J, Mangino, Massimo, Stevens, Suzanne, Thompson, John R, Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W, Nimmo, Elaine R, Satsangi, Jack, Fisher, Sheila A, Forbes, Alastair, Lewis, Cathryn M, Onnie, Clive M, Prescott, Natalie J, Sanderson, Jeremy, Matthew, Christopher G, Barbour, Jamie, Mohiuddin, M Khalid, Todhunter, Catherine E, Mansfield, John C, Ahmad, Tariq, Cummings, Fraser R, Jewell, Derek P, Webster, John, Brown, Morris J, Lathrop, Mark G, Connell, John, Dominiczak, Anna, Marcano, Carolina A Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L, Munroe, Patricia B, Newhouse, Stephen J, Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N, Donovan, Hannah, Eyre, Steve, Gilbert, Paul D, Hilder, Samantha L, Hinks, Anne M, John, Sally L, Potter, Catherine, Silman, Alan J, Symmons, Deborah PM, Thomson, Wendy, Worthington, Jane, Dunger, David B, Widmer, Barry, Frayling, Timothy M, Freathy, Rachel M, Lango, Hana, Perry, John R B, Shields, Beverley M, Weedon, Michael N, Hattersley, Andrew T, Hitman, Graham A, Walker, Mark, Elliott, Kate S, Groves, Christopher J, Lindgren, Cecilia M, Rayner, Nigel W, Timpson, Nicolas J, Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V S, Bradbury, Linda A, Farrar, Claire, Pointon, Jennifer J, Wordsworth, Paul, Brown, Matthew A, Franklyn, Jayne A, Heward, Joanne M, Simmonds, Matthew J, Gough, Stephen CL, Seal, Sheila, Stratton, Michael R, Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J, Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A, Bumpstead, Suzannah J, Chaney, Amy, Downes, Kate, Ghori, Mohammed JR, Gwilliam, Rhian, Hunt, Sarah E, Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J, Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingeleif B, Howie, Bryan N, Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, Mitchell, Sarah L, Newby, Paul R, Brand, Oliver J, Carr-Smith, Jackie, Pearce, Simon H S, Gough, Stephen C L, McGinnis, R, Keniry, A, Deloukas, P, Reveille, John D, Zhou, Xiaodong, Sims, Anne-Marie, Dowling, Alison, Taylor, Jacqueline, Doan, Tracy, Davis, John C, Savage, Laurie, Ward, Michael M, Learch, Thomas L, Weisman, Michael H, Burton, Paul R, Clayton, David G, Cardon, Lon R, Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P, McCarthy, Mark I, Ouwehand, Willem H, Samani, Nilesh J, Todd, John A, Donnelly (Chair), Peter, Barrett, Jeffrey C, Davison, Dan, Donnelly, Peter, Easton, Doug, Evans, David M, Leung, Hin-Tak, Marchini, Jonathan L, Morris, Andrew P, Spencer, Chris CA, Tobin, Martin D, Attwood, Antony P, Boorman, James P, Cant, Barbara, Everson, Ursula, Hussey, Judith M, Jolley, Jennifer D, Knight, Alexandra S, Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V, Stevens, Helen E, Taylor, Niall C, Walters, Graham R, Walker, Neil M, Watkins, Nicholas A, Winzer, Thilo, Jones, Richard W, McArdle, Wendy L, Ring, Susan M, Strachan, David P, Pembrey, Marcus, Breen, Gerome, Clair, David St, Caesar, Sian, Gordon-Smith, Katharine, Jones, Lisa, Fraser, Christine, Green, Elaine K, Grozeva, Detelina, Hamshere, Marian L, Holmans, Peter A, Jones, Ian R, Kirov, George, Moskivina, Valentina, Nikolov, Ivan, O'Donovan, Michael C, Owen, Michael J, Collier, David A, Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H, Ferrier, I Nicol, Ball, Stephen G, Balmforth, Anthony J, Barrett, Jennifer H, Bishop, Timothy D, Iles, Mark M, Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S, Braund, Peter S, Dixon, Richard J, Mangino, Massimo, Stevens, Suzanne, Thompson, John R, Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W, Nimmo, Elaine R, Satsangi, Jack, Fisher, Sheila A, Forbes, Alastair, Lewis, Cathryn M, Onnie, Clive M, Prescott, Natalie J, Sanderson, Jeremy, Matthew, Christopher G, Barbour, Jamie, Mohiuddin, M Khalid, Todhunter, Catherine E, Mansfield, John C, Ahmad, Tariq, Cummings, Fraser R, Jewell, Derek P, Webster, John, Brown, Morris J, Lathrop, Mark G, Connell, John, Dominiczak, Anna, Marcano, Carolina A Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L, Munroe, Patricia B, Newhouse, Stephen J, Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N, Donovan, Hannah, Eyre, Steve, Gilbert, Paul D, Hilder, Samantha L, Hinks, Anne M, John, Sally L, Potter, Catherine, Silman, Alan J, Symmons, Deborah PM, Thomson, Wendy, Worthington, Jane, Dunger, David B, Widmer, Barry, Frayling, Timothy M, Freathy, Rachel M, Lango, Hana, Perry, John R B, Shields, Beverley M, Weedon, Michael N, Hattersley, Andrew T, Hitman, Graham A, Walker, Mark, Elliott, Kate S, Groves, Christopher J, Lindgren, Cecilia M, Rayner, Nigel W, Timpson, Nicolas J, Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V S, Bradbury, Linda A, Farrar, Claire, Pointon, Jennifer J, Wordsworth, Paul, Brown, Matthew A, Franklyn, Jayne A, Heward, Joanne M, Simmonds, Matthew J, Gough, Stephen CL, Seal, Sheila, Stratton, Michael R, Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J, Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A, Bumpstead, Suzannah J, Chaney, Amy, Downes, Kate, Ghori, Mohammed JR, Gwilliam, Rhian, Hunt, Sarah E, Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J, Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingeleif B, Howie, Bryan N, Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, Mitchell, Sarah L, Newby, Paul R, Brand, Oliver J, Carr-Smith, Jackie, Pearce, Simon H S, Gough, Stephen C L, McGinnis, R, Keniry, A, Deloukas, P, Reveille, John D, Zhou, Xiaodong, Sims, Anne-Marie, Dowling, Alison, Taylor, Jacqueline, Doan, Tracy, Davis, John C, Savage, Laurie, Ward, Michael M, Learch, Thomas L, and Weisman, Michael H

Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

42. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Nicol Ferrier, I., Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A, Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Mark Lathrop, G., Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., Donnelly, Peter, Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Nicol Ferrier, I., Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A, Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Mark Lathrop, G., Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., and Donnelly, Peter

Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

43. A Genome-Wide Assessment of the Genetic Basis of Type 1 Diabetes and Its Biology.

Author

Todd, John A., Clayton, David G., Downes, Kate, Dunger, David B., Guja, Cristian, Leung, Hin-Tak, Nutland, Sarah, Plagnol, Vincent, Smyth, Deborah J., Stevens, Helen E., Ionescu-Tirgoviste, Constantin, Tuomilehto, Jaakko, Walker, Neil M., and Widmer, Barry

Subjects
DIABETES, GENES, GENOMES, BIOLOGY, CHROMOSOMES, MAJOR histocompatibility complex, INTERFERONS, CYTOKINES
Abstract

The strong familial clustering of autoimmune type 1 diabetes in families remains only partially explained. The six confirmed genes or chromosome regions with convincing statistical support (P < 10[sup-9]) in large, and multiple, populations, namely the major histocompatibility complex (MHC), the insulin gene (INS), CTLA4, PTPN22, IL2RA/CD25, and the interferon-induced helicase 1 gene region (IFIH1/MDA5), can explain only about 50% of familial aggregation. Nonetheless, their identification has provided many insights into the biology and pathways of type I diabetes, often closely mirroring findings in the spontaneous animal models of the disease. Recent expansions in sample collections, including the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory (JDRF/WT DIL) British T1D case sample (n = 8,000), and advances in affordable, genome-wide, high throughput single nucleotide polymorphism (SNP) genotyping technologies (Affymetrix), has allowed an association analysis of 500,000 SNPs across the genome in 2,000 type 1 diabetes cases and 3,000 controls as part of the Wellcome Trust Case-Control Consortium (WTCCC). Attesting to the quality of the SNP map, positive results were obtained for all six susceptibility loci reported previously. However, follow-up genotyping studies of 14 other chromosome regions showing P < 10[sup-5] in the WTCCC scan in over 6,000 cases and 6,000 controls, and in approximately 2,000 families, supported in a convincing way (P < l0[sup-15] and odds ratios approximately 1.2) three new regions associated with type 1 diabetes in both the family and case-control samples, on chromosomes 16p13 (rs12708716), 12q13 (rs11171739) and 12q24 (rs17696736). The chromosome 12 loci map to regions of linkage disequilibrium containing many genes, although the chromosome 16p13 locus maps to a region containing two functional candidate genes, MHC2TA, which regulates HLA class II expression and the suppressor of cytokine signalling gene, SOCS1, and the third gene of unknown function, KIAA0350. These results illustrate how powerful the genome-wide association approach is in the systematic characterisation of the genetic basis of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Published
2007

44. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

Author

Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop MG, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hilder SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Newport M, Sirugo G, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Davison D, Ferreira T, Pereira-Gale J, Hallgrimsdo'ttir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Brown MA, Compston A, Farrall M, Hall AS, Hattersley AT, Hill AV, Parkes M, Pembrey M, Stratton MR, Mitchell SL, Newby PR, Brand OJ, Carr-Smith J, Pearce SH, McGinnis R, Keniry A, Deloukas P, Reveille JD, Zhou X, Sims AM, Dowling A, Taylor J, Doan T, Davis JC, Savage L, Ward MM, Learch TL, Weisman MH, and Brown M

Subjects
Aminopeptidases genetics, Breast Neoplasms epidemiology, Case-Control Studies, Chromosome Mapping, Genetics, Population, Genotype, Haplotypes genetics, Humans, Linkage Disequilibrium, Minor Histocompatibility Antigens, Multiple Sclerosis epidemiology, North America epidemiology, Polymerase Chain Reaction, Receptors, Immunologic genetics, Receptors, Interleukin genetics, Spondylitis, Ankylosing epidemiology, Thyroiditis, Autoimmune epidemiology, Autoimmunity genetics, Breast Neoplasms genetics, Multiple Sclerosis genetics, Polymorphism, Single Nucleotide genetics, Spondylitis, Ankylosing genetics, Thyroiditis, Autoimmune genetics
Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Published
2007
Full Text
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45. Interaction analysis of the CBLB and CTLA4 genes in type 1 diabetes.

Author

Payne F, Cooper JD, Walker NM, Lam AC, Smink LJ, Nutland S, Stevens HE, Hutchings J, and Todd JA

Subjects
Animals, CTLA-4 Antigen, Case-Control Studies, Denmark, Gene Frequency, Genetic Predisposition to Disease, Genetic Testing, Humans, Polymorphism, Single Nucleotide genetics, Rats, Adaptor Proteins, Signal Transducing genetics, Antigens, CD genetics, Antigens, Differentiation genetics, Diabetes Mellitus, Type 1 genetics, Proto-Oncogene Proteins c-cbl genetics
Abstract

Gene-gene interaction analyses have been suggested as a potential strategy to help identify common disease susceptibility genes. Recently, evidence of a statistical interaction between polymorphisms in two negative immunoregulatory genes, CBLB and CTLA4, has been reported in type 1 diabetes (T1D). This study, in 480 Danish families, reported an association between T1D and a synonymous coding SNP in exon 12 of the CBLB gene (rs3772534 G>A; minor allele frequency, MAF=0.24; derived relative risk, RR for G allele=1.78; P=0.046). Furthermore, evidence of a statistical interaction with the known T1D susceptibility-associated CTLA4 polymorphism rs3087243 (laboratory name CT60, G>A) was reported (P<0.0001), such that the CBLB SNP rs3772534 G allele was overtransmitted to offspring with the CTLA4 rs3087243 G/G genotype. We have, therefore, attempted to obtain additional support for this finding in both large family and case-control collections. In a primary analysis, no evidence for an association of the CBLB SNP rs3772534 with disease was found in either sample set (2162 parent-child trios, P=0.33; 3453 cases and 3655 controls, P=0.69). In the case-only statistical interaction analysis between rs3772534 and rs3087243, there was also no support for an effect (1994 T1D affected offspring, and 3215 cases, P=0.92). These data highlight the need for large, well-characterized populations, offering the possibility of obtaining additional support for initial observations owing to the low prior probability of identifying reproducible evidence of gene-gene interactions in the analysis of common disease-associated variants in human populations.

Published
2007
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