Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Serra, Eva Goncalves; Schwerd, Tobias; Moutsianas, Loukas; Cavounidis, Athena; Fachal, Laura; Pandey, Sumeet; Kammermeier, Jochen; Croft, Nicholas M.; Posovszky, Carsten; Rodrigues, Astor; Russell, Richard K.; Barakat, Farah; Auth, Marcus K. H.; Heuschkel, Robert; Zilbauer, Matthias; Fyderek, Krzysztof; Braegger, Christian; Travis, Simon P.; Satsangi, Jack; Parkes, Miles; Thapar, Nikhil; Ferry, Helen; Matte, Julie C.; Gilmour, Kimberly C.; Wedrychowicz, Andrzej; Sullivan, Peter; Moore, Carmel; Sambrook, Jennifer; Ouwehand, Willem; Roberts, David; Danesh, John; Baeumler, Toni A.; Fulga, Tudor A.; Karaminejadranjbar, Mohammad; Ahmed, Ahmed; Wilson, Rachel; Barrett, Jeffrey C.; Elkadri, Abdul; Griffiths, Anne M.; Snapper, Scott B.; Shah, Neil; Muise, Aleixo M.; Wilson, David C.; Uhlig, Holm H.; Anderson, Carl A.; Zurek, Marlen; Strisciuglio, Caterina; Elawad, Mamoun; Lo, Bernice; Arancibia-Carcamo, Carolina; Bailey, Adam; Barnes, Ellie; Bird-Lieberman, Elizabeth Louise; Brain, Oliver; Braden, Barbara; Collier, Jane; East, James; Howarth, Lucy; Keshav, Satish; Klenerman, Paul; Leedham, Simon; Palmer, Rebecca; Powrie, Fiona; Simmons, Alison; Walker, Matthew; Tolkien, Zoe; Kaptoge, Stephen; Allen, David; Mehenny, Susan; Mant, Jonathan; Di Angelantonio, Emanuele; Thompson, Simon G.; Yilmaz, Bahtiyar; Juillerat, Pascal; Geuking, Markus; Wiest, Reiner; Macpherson, Andrew J.; Bravo, Francisco Damian; Brugger, Lukas; Carstens, Ove; Bigler, Ulrike Graf; Heimgartner, Benjamin; Rusticeanu, Monica; Schmid-Uebelhart, Sybille; Strebel, Bruno; Tatu, Aurora; Tutuian, Radu; Wiest, Reiner; Oyas, Ove; Ramon, Charlotte; Stelling, Jorg; Franc, Yannick; Fournier, Nicolas; Pittet, Valerie E. H.; Burnand, Bernard; Egger, Mara; Franc, Yannick; Golay, Delphine; Marot, Astrid; Musso, Leilla; Pittet, Valerie; Rossel, Jean-Benoit; Seematter, Vivianne; Sommer, Joachim; Vulliamy, Rachel; Michetti, Pierre; Maillard, Michel H.; Keller, Celine; Maillard, Michel H.; Nydegger, Andreas; Schoepfe, Alain; Archanioti, Eva; Ezri, Jessica; Fraga, Montserrat; Schoepfer, Alain; Müller, Christoph; Rogler, Gerhard; Biedermann, Luc; Blattmann, Mirjam; Burk, Sabine; Dora, Barbara; Fried, Michael; Misselwitz, Benjamin; Mullhaupt, Beat; Obialo, Nicole; Pohl, Daniel; Raschle, Nadia; Rogler, Gerhard; Scharl, Michael; Vavricka, Stephan; Kanel, Roland von; Zeitz, Jonas; Abdelrahman, Karim; Ademi, Gentiana; Borovicka, Jan; Brand, Stephan; Frei, Remus; Haarer, Johannes; -Grieger, Christina Knellwolf; Krieger-Grubel, Claudia; Kunzler, Patrizia; Meyenberger, Christa; Meyer, Pamela; Rohrich, Nina; Sawatzki, Mikael; Schelling, Martin; Semadeni, Gian-Marco; Sulz, Michael; Zimmermann, Dorothee; Aepli, Patrick; Criblez, Dominique H.; Hess, Cyrill; Richterich, Jean-Pierre; Spalinger, Johannes; Staudenmann, Dominic; Stulz, Andreas; Wohrle, Stefanie; Thomas, Amman; Anderegg, Claudia; Kohler, Henrik; Kusche, Rachel; Antonino, Anca-Teodora; Arrigoni, Eviano; Bengoa, Jose M.; Cunningham, Sophie; de Saussure, Philippe; Girard, Laurent; Bakker de Jong, Diana; Basturk, Polat; Brunner, Simon; Degen, Lukas; Hruz, Petr; Khalid-de Bakker, Carolina; Niess, Jan; Balsiger, Bruno; Haldemann, Janine; Saner, Gaby; Seibold, Frank; Bauerfeind, Peter; Becocci, Andrea; Belli, Dominique; Binek, Janek; Hengstler, Peter; Boehm, Stephan; Boldanov, Tujana; Buhr, Patrick; Koller, Rebekka; Rueger, Vanessa; Senning, Arne; Burri, Emanuel; Buyse, Sophie; Cao, Dahlia-Thao; D'Angelo, Fabrizia; Delarive, Joakim; Doerig, Christopher; Hessler, Roxane; Preissler, Claudia; Rentsch, Ronald; Risti, Branislav; Ritz, Marc Alain; Steuerwald, Michael; Vogtlin, Jurg; Sagmeister, Markus; Sauter, Bernhard; Schibli, Susanne; Sokollik, Christiane; Spalinger, Johannes; Schlauri, Hugo; Schnegg, Jean-Francois; Seirafi, Mariam; Spangenberger, Holger; Stadler, Philippe; Staub, Peter; Stenz, Volker; Tempia-Caliera, Michela; Thorens, Joel; Truninger, Kaspar; Urfer, Patrick; Viani, Francesco; Vouillamoz, Dominique; Zander, Silvan; Wyli, Tina; Jostins, L.; Kennedy, N. A.; Ahmad, T.; Lamb, C. A.; Edwards, C.; Hart, A.; Hawkey, C.; Mansfield, J. C.; Mowat, C.; Newman, W. G.; Simmons, A.; Tremelling, M.; Lee, J. C.; Prescott, N. J.; Mathew, C. G.; Lees, C. W.; McGovern, D. P. B.; Targan, S. R.; Botwin, G.; Mengesha, E.; Fleshner, P.; Landers, C.; Li, D.; Rioux, J. D.; Bitton, A.; Cote-Daigneault, J.; Daly, M. J.; Xavier, R.; Morris, K.; Boucher, G.; Cho, J. H.; Abraham, C.; Merad, M.; Sands, B.; Peter, I.; Hao, K.; Itan, Y.; Duerr, R. H.; Konnikova, L.; Schwartz, M. B.; Proksell, S.; Johnston, E.; Miladinova, V.; Chen, W.; Brant, S. R.; Datta, L.; Silverberg, M. S.; Schumm, L. P.; Birch, S.; Giri, M.; Gettler, K.; Sharma, Y.; Stevens, C.; Lazarev, M.; Haritunians, T. (2020): Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. In: Nature Communications, Vol. 11, No. 1, 995

Abstract

Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in similar to 70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls;P<4x10(-10)), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls;P<5x10(-10)). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2041-1723
• Language: English