Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers

Suna Onengut-Gumuscu, Wei Min Chen, Oliver Burren, Nick J. Cooper, Aaron R. Quinlan, Josyf C. Mychaleckyj, Emily Farber, Jessica K. Bonnie, Michal Szpak, Ellen Schofield, Premanand Achuthan, Hui Guo, Mary D. Fortune, Helen Stevens, Neil M. Walker, Lucas D. Ward, Anshul Kundaje, Manolis Kellis, Mark J. Daly, Jeffrey C. BarrettJason D. Cooper, Panos Deloukas, John A. Todd, Chris Wallace, Patrick Concannon, Stephen S. Rich, Tracey Baskerville, Nines Bautista, Eesh Bhatia, Vijayalakshmi Bhatia, Kamaruzaman Bin Hasan, Francois Bonnici, Thomas Brodnicki, Brian Browning, Fergus Cameron, Katharee Chaichanwatanakul, Pik To Cheung, Peter Colman, Andrew Cotterill, Jenny Couper, Patricia Crock, Ric Cutfield, Tim Davis, Paul Dixon, Kim Donaghue, Katrina Dowling, Paul Drury, Sarah Dye, Shane Gellert, Rohana Abdul Ghani, Ristan Greer, Xueyao Han, Len Harrison, Nick Homatopoulos, Linong Ji, Tim Jones, Loke Kah Yin, Nor Azmi Kamaruddin, Uma Kanga, Alok Kanungo, Gurvinder Kaur, Betty Kek, Simon Knowles, Jeremy Krebs, Neeraj Kumar, Yann Jinn Lee, Xiaoying Li, Supawadee Liktimaskul, Margaret Lloyd, Amanda Loth, Anthony Louey, Narinder Mehra, Tony Merriman, Liu Min, Grant Morahan, Robert Moses, Grant Mraz, Rinki Murphy, Ian Nicholson, Araceli Panelo, Perlita Poh, Gareth Price, Nirubasini Ratnam, Carani Sanjeevi, Saikiran Sedimbi, Shuixian Shen, Goh Siok Ying, Brian Tait, Nikhil Tandon, Allison Thomas, Mike Varney, Praewvarin Weerakulwattana, Jinny Willis, Elvis Abang Akwo, Lotte Albret, Francisco Ampudia-Blasco, Jesus Argente, Magdalena Avbelj, Gulja Babadjanova, Klaus Badenhoop, Tadej Battelino, Georg Beilhack, Regine Bergholdt, Polly Bingley, Bernhard Boehm, Jo Bolidson, Kerstin Brismar, Caroline Brorsson, Joyce Carlson, Luis Castano, Kyla Chandler, Valentino Cherubini, Ondrej Cinek, Elisa Cipponeri, Raquel Corripio Collado, Alberto de Leiva, Iveta Dzivite, Ana Fagulha, Merce Fernandez Balcells, Beatriz Garcia Cuartero, Concepcion Garcia Lacalle, Cristian Guja, Pilar Gutiérrez, Alona Hamou, Erifili Hatziagelaki, Simon Heath, Kaire Heilman, Wolfgang Helmberg, Orna Hermon, Marta Hernandez, Iris Holzheu, Nora Hosszufalusi, Jorma Ilonen, Constantin Ionescu-Tirgoviste, Jesper Johannesen, Cecile Julier, Heinrich Kahles, Ida Kinalska, Mikael Knip, Ingrid Kockum, Eija Kojo, Olga Kordonouri, Adam Kretowski, Dora Krikovszky, Angelika Kurkhaus, Madiusz Kuzmicki, Eva Lavant, Anna Long, Johnny Ludvigsson, Laszlo Madacsy, Katarzyna Maliszewska, Mara Marga, Marissa Penna Martinez, Didac Mauricio, Gertrud Mazurkievicz, Jorn Nerup, Antanas Norkus, Francisco Javier Novoa Mogollon, Anna Okruszko, Chiara Pettinari, Moshe Phillip, Valdis Pirags, Flemming Pociot, Paolo Pozzilli, Radu Racasan, Klemens Raile, Rebecca Rappner, Maria Jesus Rodriguez Troyano, Bart O. Roep, Saba Rokni, Silke Rosinger, Oscar Rubio-Cabezas, Christa Ruckgaber, Ilhan Satman, Edith Schober, Jochen Seufert, Rosi Sing, Jan Skrha, Eugene Sobngwi, Michelle Somerville, Giatgen Spinas, Zdenek Sumnik, Vallo Tilmann, Dag Undlien, Vaidotas Urbanavicius, Bart Van der Auwera, Federico Vasquez San Miguel, Andriani Vazeo-Gerasimidi, Dzilda Velickiene, Ana Wägner, Markus Walter, Alistair Williams, Anette Ziegler, Matthew Agleham, Alan Aldrich, Ramin Alemzadeh, Chester Alper, Theresa Aly, Dimitris Anastassiou, Shaily Arora, Audrey Austin, Dorothy Becker, Christophe Benoist, Noureddine Berka, Suruchi Bhatia, Persia Bonella, Nunzio Bottini, Sean Boyle, Jeanah Braden, Barry Brady, Wendy Brickman, Richard Christensen, Robert Couch, Debra Counts, Jill Crandall, Mark Daniels, Larry Dolan, David Donaldson, Alessandro Doria, George Eisenbarth, James Elder, Rita El-Hajj, Henry Erlich, Pamela Fain, Anna Lisa Fear, Robert Ferry, Rosanna Fiallo-Scharer, Daniel Geraghty, Soumitra Ghosh, Steven Gitelman, Michelle Godwin, Robin Goland, Nathan Goodman, Greg Goodwin, Jenna Gravely, Carla Greenbaum, Chelsea Gudgeon, Fred Gunville, William Hagopian, Hakon Hakonarson, John Hansen, Kimberly Harrington, Jeanne Hassing, Wendy Hilliker, Robert Hoffman, Erin Hulbert, Roberto Izquierdo, Nicholas Jospe, Kevin Kaiserman, Francine Kaufman, Samuel Kim, Erin Kloos, Roman Kosoy, James Lane, Julie Lane, Jean Lawrence, Claresa Levetan, Phil Levin, Rebecca Lipton, John Lonsdale, Victoria Magnuson, Jennifer Marks, Beth Mayer-Davis, Robert McEvoy, Richard McIndoe, Lesley Merkle, Daniel Metzger, Dongmei Miao, Eric Mickelson, Priscilla Moonsamy, Wayne Moore, Antoinette Moran, Janelle Noble, Gary Olsem, Tihamer Orban, Craig Orlowski, Andrew Paterson, Massimo Pietropaolo, Catherine Pihoker, Constantin Polychronakos, Jeff Post, Daniel Postellon, Alberto Pugliese, Hui Qi Qu, Teresa Quattrin, Mark Rappaport, Philip Raskin, Heather Risbeck, Henry Rodriguez, Luisa Rodriguez, Michelle Rogers, Leticia Rubalcava, Bill Russell, Desmond Schatz, Carla Scott, Jin Xiong She, Heather Shilling, Dorothy Shulman, Leslie Soyka, Phyllis Speiser, Harold Starkman, Andrea Steck, Sarah Stender, Lorraine Stratton, Daniel Sur, Shayne Taback, Kathryn Thrailkill, Ellen Toth, Patricia Trymbiski, Eva Tsalikian, Katherine Vertachnik, Jack Wahlen, Xujing Wang, Sandra Weber, Diane Wherrett, Steven Willi, Darrell Wilson, Jerry Youkey, Neal Young, Liping Yu, Lue Ping Zhao, Donald Zimmerman, Ellen Adlem, James Allen, Judy Brown, Pamela Clarke, David Clayton, Gillian Coleman, Francesco Cucca, Lucy Davison, Kate Downes, Simon Duley, David Dunger, Laura Esposito, Vin Everett, Sarah Field, Jason Hafler, Matthew Hardy, Deborah Harrison, Inge Harrison, Steve Hawkins, Barry Healy, Simon Hood, Simon Howell, Joanna Howson, Meeta Maisuria, William Meadows, Trupti Mistry, Sergey Nezhenstsev, Sarah Nutland, Nigel Ovington, Vincent Plagnol, Dan Rainbow, Kara Rainbow, Srilakshmi Raj, Helen Schuilenburg, Anna Simpson, Luc Smink, Debbie Smyth, Niall Taylor, Jaakko Tuomilehto, Linda Wicker, Barry Widmer, Mark Wilson, Heather Withers, Jennie Yang, Mark Brown, Arnetta Crews, Jason Griffin, Mark Hall, Teresa Harnish, John Hepler, Joan Hilner, Nancy King, Kurt Lohman, Lingyi Lu, Jay Nail, Letitia Perdue, June Pierce, David Reboussin, Scott Rushing, Michele Sale, Elizabeth Sides, Beverly Snively, Hoa Teuschler, Goodrich Theil, Lynne Wagenknecht, Dustin Williams, Beena Akolkar, Catherine McKeon, Concepcion Nierras, Elizabeth Thomson, David Altshuler, Kinman Au, Steve Bain, Lisa Barcellos, Sandra Barral, Tim Becker, Farren Briggs, Paola Bronson, Paul de Bakker, Bernie Devlin, Morten Chrisoph Eike, Leigh Field, Stacey Gabriel, Nikhil Garge, Silvana Gaudieri, Ben Goldstein, Clara Gorodezky, Sara Hamon, Chungsheng He, Joanna Howson, Keith Humphreys, Ian James, Mark Lathrop, Benedicte Alexandra Lie, Dawei Li, Steven Mack, Ralph McGinnis, Elizabeth McKinnon, William McLaren, David Nolan, Marita Olsson, Jurg Ott, David Owerbach, Chris Patterson, Robert Podolsky, Patricia Ramsay, Venkatesh Rangantah, Neil Risch, Kjersti Skjold Ronningen, Xiarong Shao, Richard Single, Michael Steffes, Glenys Thomson, Ana Maria Valdes, Claire Vandiedonck, Pam Whittaker, Qingrun Zhang

Research output: Contribution to journalArticle

257 Scopus citations

Abstract

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10-8). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34 + stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.

Original languageEnglish (US)
Pages (from-to)381-386
Number of pages6
JournalNature Genetics
Volume47
Issue number4
DOIs
StatePublished - Apr 28 2015

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