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1. HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Author

Akar, Alaa, Flemming, Cornelius, Felix, Flomm, Flosbach, Markus, Jäger, Julia, Jeromin, Niklas, Jung, Johannes, Ohms, Mareike, Reinshagen, Konrad, Rische, Johann, Sagebiel, Adrian, Sandfort, Deborah, Steinert, Fenja, Tomuschat, Christian, Wesche, Jasmin, Shifteh Abedian, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Alberts, Rudi, Alizadeh, Behrooz, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Annese, Vito, Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Bampton, Peter A., Barclay, Murray, Barrett, Jeffrey C., Bethge, Johannes, Bewshea, Claire, Bis, Joshua C., Bitton, Alain, BK, Thelma, Boucher, Gabrielle, Brain, Oliver, Brand, Stephan, Brant, Steven R., Cheon, Jae Hee, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Cooney, Rachel, Croft, Anthony, Daly, Mark J., D'Amato, Mauro, Danese, Silvio, Daryani, Naser Ebrahim, Datta, Lisa Wu, Degenhardt, Frauke, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Drummond, Hazel E., Dubinsky, Marla, Duerr, Richard H., Edwards, Cathryn, Ellinghaus, David, Ellul, Pierre, Esaki, Motohiro, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Franke, Andre, Fuyuno, Yuta, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Goyette, Philippe, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Hold, Georgina L., Hong, Myhunghee, Hu, Xinli, Huang, Hailiang, Hugot, Jean-Pierre, Hui, Ken Y., Imielinski, Marcin, Jazayeri, Omid, Jonaitis, Laimas, Jostins, Luke, Juyal, Garima, Chandra Juyal, Ramesh, Kalla, Rahul, Karlsen, Tom H., Kennedy, Nicholas A., Khan, Mohammed Azam, Kim, Won Ho, Kitazono, Takanari, Kiudelis, Gediminas, Kubo, Michiaki, Kugathasan, Subra, Kupcinskas, Limas, Lamb, Christopher A., de Lange, Katrina M., Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Lewis, Nina, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Luo, Yang, Mahy, Gillian, Malekzadeh, Masoud Mohammad, Malekzadeh, Reza, Mansfield, John, Marriott, Suzie, Massey, Dunecan, Mathew, Christopher G., Matsui, Toshiyuki, McGovern, Dermot P.B., van der Meulen, Andrea, Midha, Vandana, Milgrom, Raquel, Mirzaei, Samaneh, Mitrovic, Mitja, Montgomery, Grant W., Mowat, Craig, Müller, Christoph, Newman, William G., Ng, Aylwin, Ng, Siew C., Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nöthen, Markus, Oikonomou, Ioannis, Okou, David, Orchard, Timothy R., Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Urõs, Poustchi, Hossein, Prescott, Natalie J., Proctor, Deborah D., Radford-Smith, Graham, Rahier, Jean- Francois, Regueiro, Miguel, Reinisch, Walter, Rieder, Florian, Rioux, John D., Roberts, Rebecca, Rogler, Gerhard, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Scharl, Michael, Schembri, John, Schreiber, Stefan, Schumm, L. Philip, Scott, Regan, Seielstad, Mark, Shah, Tejas, Sharma, Yashoda, Silverberg, Mark S., Simmons, Alison, Simms, Lisa A., Singh, Abhey, Skieceviciene, Jurgita, van Sommeren, Suzanne, Song, Kyuyoung, Sood, Ajit, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sung, Joseph J.Y., Targan, Stephan R., Taylor, Kirstin M., Theatre, Emilie, Torkvist, Leif, Torres, Esther A., Tremelling, Mark, Uhlig, Holm H., Umeno, Junji, Vahedi, Homayon, Vasiliauskas, Eric, Velde, Anje ter, Ventham, Nicholas T., Vermeire, Severine, Verspaget, Hein W., De Vos, Martine, Walters, Thomas, Wang, Kai, Wang, Ming-Hsi, Weersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Wong, Sunny H., Xavier, Ramnik J., Yamazaki, Keiko, Yang, Suk-Kyun, Ye, Byong Duk, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wei, Zhao, Hongyu, Zhao, Zhen Z., Baumdick, Martin E., Niehrs, Annika, Schwerk, Maria, Hinrichs, Ole, Jordan-Paiz, Ana, Padoan, Benedetta, Wegner, Lucy H.M., Schloer, Sebastian, Zecher, Britta F., Malsy, Jakob, Joshi, Vinita R., Illig, Christin, Schröder-Schwarz, Jennifer, Möller, Kimberly J., Martin, Maureen P., Yuki, Yuko, Ozawa, Mikki, Sauter, Jürgen, Schmidt, Alexander H., Perez, Daniel, Giannou, Anastasios D., Carrington, Mary, Davis, Randall S., Schumacher, Udo, Sauter, Guido, Huber, Samuel, Puelles, Victor G., Melling, Nathaniel, Altfeld, Marcus, and Bunders, Madeleine J.

Published
2023
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2. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Author

Jostins, Luke, Ripke, Stephan, Weersma, Rinse K, Duerr, Richard H, McGovern, Dermot P, Hui, Ken Y, Lee, James C, Philip Schumm, L, Sharma, Yashoda, Anderson, Carl A, Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L, Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N, Andersen, Vibeke, Andrews, Jane M, Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A, Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D’Amato, Mauro, De Jong, Dirk, Devaney, Kathy L, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R, Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Hu, Xinli, Karlsen, Tom H, Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C, Lees, Charlie W, Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R, Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y, Potocnik, Uros, Prescott, Natalie J, Regueiro, Miguel, Rotter, Jerome I, Russell, Richard K, Sanderson, Jeremy D, Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A, Sventoraityte, Jurgita, Targan, Stephan R, Taylor, Kent D, Tremelling, Mark, Verspaget, Hein W, De Vos, Martine, Wijmenga, Cisca, Wilson, David C, Winkelmann, Juliane, Xavier, Ramnik J, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K, Zhao, Hongyu, Silverberg, Mark S, Annese, Vito, Hakonarson, Hakon, Brant, Steven R, Radford-Smith, Graham, Mathew, Christopher G, Rioux, John D, and Schadt, Eric E

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Crohn's Disease, Human Genome, Autoimmune Disease, Inflammatory Bowel Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Haplotypes, Host-Pathogen Interactions, Humans, Inflammatory Bowel Diseases, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, International IBD Genetics Consortium, General Science & Technology
Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Published
2012

3. Increased Effectiveness of Early Therapy With Anti-Tumor Necrosis Factor-α vs an Immunomodulator in Children With Crohn's Disease

Author

Walters, Thomas D., Kim, Mi-Ok, Denson, Lee A., Griffiths, Anne M., Dubinsky, Marla, Markowitz, James, Baldassano, Robert, Crandall, Wallace, Rosh, Joel, Pfefferkorn, Marian, Otley, Anthony, Heyman, Melvin B., LeLeiko, Neal, Baker, Susan, Guthery, Stephen L., Evans, Jonathan, Ziring, David, Kellermayer, Richard, Stephens, Michael, Mack, David, Oliva-Hemker, Maria, Patel, Ashish S., Kirschner, Barbara, Moulton, Dedrick, Cohen, Stanley, Kim, Sandra, Liu, Chunyan, Essers, Jonah, Kugathasan, Subra, and Hyams, Jeffrey S.

Published
2014
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4. Early nasal continuous positive airway pressure and necrotizing enterocolitis in preterm infants

Author

Aly, Hany, Massaro, An N., Hammad, Tarek A., Narang, Sherry, and Essers, Jonah

Subjects
Continuous positive airway pressure -- Usage, Continuous positive airway pressure -- Health aspects, Enterocolitis, Neonatal necrotizing -- Care and treatment, Enterocolitis, Pseudomembranous -- Care and treatment, Birth weight, Low -- Care and treatment, Children -- Diseases, Children -- Care and treatment
Published
2009

6. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Author

Goyette, Philippe, Boucher, Gabrielle, Mallon, Dermot, Ellinghaus, Eva, Jostins, Luke, Huang, Hailiang, Ripke, Stephan, Gusareva, Elena S., Annese, Vito, Hauser, Stephen L., Oksenberg, Jorge R., Thomsen, Ingo, Leslie, Stephen, Daly, Mark J., Van Steen, Kristel, Duerr, Richard H., Barrett, Jeffrey C., Mcgovern, Dermot P. B., Schumm, L. Philip, Traherne, James A., Carrington, Mary N., Kosmoliaptsis, Vasilis, Karlsen, Tom H., Franke, Andre, Rioux, John D., Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Balschun, Tobias, Bampton, Peter A., Barclay, Murray, Bayless, Theodore M., Bethge, Johannes, Bis, Joshua C., Bitton, Alain, Brand, Stephan, Brant, Steven R., Buning, Carsten, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Croft, Anthony, D'Amato, Mauro, Danese, Silvio, De Jong, Dirk, De Vos, Martine, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jurgen, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Xinli, Hu, Hui, Ken Y., Imielinski, Marcin, Ippoliti, Andrew, Jonaitis, Laimas, Kennedy, Nicholas A., Khan, Mohammed Azam, Kiudelis, Gediminas, Kugathasan, Subra, Kupcinskas, Limas, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Mahy, Gillian, Mansfield, John, Massey, Dunecan, Mathew, Christopher G., Milgrom, Raquel, Mitrovic, Mitja, Montgomery, Grant, Mowat, Craig, Newman, Wwilliam, Aylwin, Ng, Siew C., Ng, Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nothen, Markus, Oikonomou, Ioannis, Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Proctor, Deborah D., Radford Smith, Graham, Rahier, Jean Francois, Raychaudhur, Soumya, Regueiro, Miguel, Rieder, Florian, Roberts, Rebecca, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Schreiber, Stefan, Scott, Regan, Seielstad, Mark, Sharma, Yashoda, Silverberg, Mark S., Simms, Lisa A., Skieceviciene, Jurgita, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kirstin M., Ter Velde, Anje, Theatre, Emilie, Torkvist, Leif, Tremelling, Mark, Van Der Meulen, Andrea, Van Sommeren, Suzanne, Vasiliauskas, Eric, Vermeire, Severine, Verspaget, Hein W., Walters, Thomas, Wwang, Kai, Wwang, Ming Hsi, Wweersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wwei, Zhao, Hongyu, Zhao, Zhen Z., Gastroenterology and Hepatology, Traherne, James [0000-0002-6003-8559], Kosmoliaptsis, Vasilis [0000-0001-7298-1387], and Apollo - University of Cambridge Repository

Subjects
Heterozygote, Genotype, Genotyping Techniques, Genetic Linkage, Ulcerative, Human leukocyte antigen, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, Primary sclerosing cholangitis, Major Histocompatibility Complex, Alleles, Chromosome Mapping, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DRB1 Chains, Humans, Inflammatory Bowel Diseases, Phenotype, Genetics, medicine, HLA-DR, Polymorphism, Colitis, HLA-DRB1, Crohn's disease, Single Nucleotide, medicine.disease, Ulcerative colitis, digestive system diseases, Immunology, biology.protein
Abstract

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Published
2015
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7. Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping

Author

Okou, David T., Mack, David, Markowitz, James, Rosh, Joel, Stephens, Michael, Prince, Jarod, Hyams, Jeffrey S., Kumar, Archana, Keljo, David J., Cutler, David J., Bohnsack, John F., Moulton, Dedrick, Kellermayer, Richard, Ramachandran, Dhanya, Heyman, Melvin B., Haberman, Yael, Pfefferkorn, Marian, Aronow, Bruce, Baldassano, Robert, Kappelman, Michael D., Griffiths, Anne M., Dubinsky, Marla, Guthery, Stephen L., Zwick, Michael E., Bose, Promita, Crandall, Wallace V., Thompson, Susan D., Walters, Thomas, Mondal, Kajari, LeLeiko, Neal, Prahalad, Sampath, and Essers, Jonah

Subjects
digestive system diseases
Abstract

BackgroundThe inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.MethodsWe performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn’s disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn’s disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.ConclusionsThe allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

Published
2015
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8. Genome-wide association identifies multiple ulcerative colitis susceptibility loci (vol 42, pg 332, 2010)

Author

McGovern, Dermot P. B., Gardet, Agnes, Törkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Loerdal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Seielstad, Mark, McGovern, Dermot P. B., Gardet, Agnes, Törkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Loerdal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., and Seielstad, Mark

Published
2011
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9. Genome-wide association identifies multiple ulcerative colitis susceptibility loci

Author

McGovern, Dermot P. B., Gardet, Agnes, Torkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Lordal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Seielstad, Mark, McGovern, Dermot P. B., Gardet, Agnes, Torkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagace, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Lordal, Mikael, Padyukov, Leonid, Andriulli, Angelo, Colombo, Elisabetta, Latiano, Anna, Palmieri, Orazio, Bernard, Edmond-Jean, Deslandres, Colette, Hommes, Daan W., de Jong, Dirk J., Stokkers, Pieter C., Weersma, Rinse K., Sharma, Yashoda, Silverberg, Mark S., Cho, Judy H., Wu, Jing, Roeder, Kathryn, Brant, Steven R., Schumm, L. Phillip, Duerr, Richard H., Dubinsky, Marla C., Glazer, Nicole L., Haritunians, Talin, Ippoliti, Andy, Melmed, Gil Y., Siscovick, David S., Vasiliauskas, Eric A., Targan, Stephan R., Annese, Vito, Wijmenga, Cisca, Pettersson, Sven, Rotter, Jerome I., Xavier, Ramnik J., Daly, Mark J., Rioux, John D., and Seielstad, Mark

Abstract

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan(1), comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

Published
2010
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10. Report of the CCFA Pediatric Bone, Growth and Muscle Health Workshop, New York City, November 11–12, 2011, With Updates

Author

Sylvester, Francisco A., primary, Gordon, Catherine M., additional, Thayu, Meena, additional, Burnham, Jon M., additional, Denson, Lee A., additional, Essers, Jonah, additional, Ferrari, Serge, additional, Gupta, Neera, additional, Hewison, Martin, additional, Koletzko, Sibylle, additional, McCabe, Laura, additional, Pappa, Helen, additional, Sanderson, Ian, additional, Ward, Leanne, additional, and Zanotti, Stefano, additional

Published
2013
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11. 829 Early Anti-TNFα Therapy Is Superior to Early Immunomodulator Therapy in Newly Diagnosed Children With Crohn's Disease

Author

Hyams, Jeffrey S., primary, Kim, Mi-Ok, additional, Denson, Lee, additional, Griffiths, Anne M., additional, Dubinsky, Marla, additional, Markowitz, James, additional, Baldassano, Robert, additional, Crandall, Wallace, additional, Rosh, Joel R., additional, Pfefferkorn, Marian D., additional, Otley, Anthony R., additional, Heyman, Melvin B., additional, Leleiko, Neal S., additional, Baker, Susan S., additional, Guthery, Stephen L., additional, Evans, Jonathan, additional, Ziring, David, additional, Kellermayer, Richard, additional, Stephens, Michael C., additional, Mack, David R., additional, Oliva-Hemker, Maria, additional, Essers, Jonah B., additional, Patel, Ashish S., additional, Kirschner, Barbara S., additional, Moulton, Dedrick E., additional, Cohen, Stanley A., additional, Liu, Chunyan, additional, Kugathasan, Subra, additional, and Walters, Thomas D., additional

Published
2013
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12. 976 Early Onset Crohn's Disease Exhibit Distinct Allele Architecture Differences and Reveal New IBD Loci

Author

Kugathasan, Subra, primary, Dubinsky, Marla, additional, Guthery, Stephen L., additional, Okou, David T., additional, Bose, Promita, additional, Zwick, Michael E., additional, Cutler, David J., additional, Waters, Jon P., additional, Hyams, Jeffrey S., additional, Baldassano, Robert, additional, Stephens, Michael C., additional, Heyman, Melvin B., additional, Griffiths, Anne M., additional, Crandall, Wallace, additional, Markowitz, James, additional, Essers, Jonah B., additional, Snapper, Scott B., additional, Walters, Thomas D., additional, Aronow, Bruce J., additional, and Denson, Lee, additional

Published
2013
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14. 138 Effect of Deep Ulceration at Diagnostic Colonoscopy on Initial Therapy and One Year Outcome in Children With Crohn's Disease

Author

Hyams, Jeffrey S., primary, Kim, Mi-Ok, additional, Denson, Lee, additional, Stephens, Michael C., additional, Markowitz, James, additional, Griffiths, Anne M., additional, Crandall, Wallace, additional, Essers, Jonah B., additional, Baldassano, Robert, additional, Dubinsky, Marla, additional, Rosh, Joel R., additional, Pfefferkorn, Marian D., additional, Kim, Sandra C., additional, Otley, Anthony R., additional, Kellermayer, Richard, additional, Heyman, Melvin B., additional, Leleiko, Neal S., additional, Baker, Susan S., additional, Guthery, Stephen L., additional, Evans, Jonathan, additional, Ziring, David, additional, Kugathasan, Subra, additional, and Walters, Thomas D., additional

Published
2012
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17. The Utility of Genetics in Classifying Ulcerative Colitis and Crohn's Disease Patients

Author

Essers, Jonah B., primary, Cole, Elisabeth B., additional, Dubinsky, Marla, additional, Haritunians, Talin, additional, Korzenik, Joshua R., additional, McGovern, Dermot P., additional, Sands, Bruce E., additional, Targan, Stephan R., additional, Taylor, Kent D., additional, Teleten, Nick, additional, Xavier, Ramnik J., additional, Daly, Mark J., additional, Rotter, Jerome I., additional, and Silverberg, Mark S., additional

Published
2011
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21. Erratum: Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

Author

McGovern, Dermot P. B., Gardet, Agnès, Törkvist, Leif, Goyette, Philippe, Essers, Jonah, Taylor, Kent D., Neale, Benjamin M., Ong, Rick T. H., Lagacé, Caroline, Li, Chun, Green, Todd, Stevens, Christine R., Beauchamp, Claudine, Fleshner, Phillip R., Carlson, Marie, D'Amato, Mauro, Halfvarson, Jonas, Hibberd, Martin L., Lördal, Mikael, and Padyukov, Leonid

Subjects
SPELLING errors
Abstract

A correction to the article "Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy," by Hyun Hor and colleagues that was published in the 2010 issue is presented.

Published
2011
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22. Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping.

Author

Cutler DJ, Zwick ME, Okou DT, Prahalad S, Walters T, Guthery SL, Dubinsky M, Baldassano R, Crandall WV, Rosh J, Markowitz J, Stephens M, Kellermayer R, Pfefferkorn M, Heyman MB, LeLeiko N, Mack D, Moulton D, Kappelman MD, Kumar A, Prince J, Bose P, Mondal K, Ramachandran D, Bohnsack JF, Griffiths AM, Haberman Y, Essers J, Thompson SD, Aronow B, Keljo DJ, Hyams JS, Denson LA, and Kugathasan S

Subjects
Adult, Age of Onset, Alleles, Base Sequence, Child, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Polymorphism, Single Nucleotide genetics, Sequence Analysis, DNA, Colitis, Ulcerative genetics, Crohn Disease genetics, Nod2 Signaling Adaptor Protein genetics, Receptors, Interleukin genetics
Abstract

Background: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent., Methods: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases., Conclusions: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.

Published
2015
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23. Common variants at five new loci associated with early-onset inflammatory bowel disease.

Author

Imielinski M, Baldassano RN, Griffiths A, Russell RK, Annese V, Dubinsky M, Kugathasan S, Bradfield JP, Walters TD, Sleiman P, Kim CE, Muise A, Wang K, Glessner JT, Saeed S, Zhang H, Frackelton EC, Hou C, Flory JH, Otieno G, Chiavacci RM, Grundmeier R, Castro M, Latiano A, Dallapiccola B, Stempak J, Abrams DJ, Taylor K, McGovern D, Silber G, Wrobel I, Quiros A, Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmuda MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwillam R, Tremelling M, Delukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ, Heyman MB, Ferry GD, Kirschner B, Lee J, Essers J, Grand R, Stephens M, Levine A, Piccoli D, Van Limbergen J, Cucchiara S, Monos DS, Guthery SL, Denson L, Wilson DC, Grant SF, Daly M, Silverberg MS, Satsangi J, and Hakonarson H

Subjects
Age of Onset, Chromosome Mapping, Colitis, Ulcerative genetics, Genome, Human, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases epidemiology, Genetic Variation, Inflammatory Bowel Diseases genetics
Abstract

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

Published
2009
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