Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
Eva Serra, Tobias Schwerd, Loukas Moutsianas, Athena Cavounidis, Laura Fachal, Sumeet Pandey, Jochen Kammermeier, Nicholas M. Croft, Carsten Posovszky, Astor Rodrigues, Richard K. Russell, Farah Barakat, Marcus Auth, Robert Heuschkel, Matthias Zilbauer, Krzysztof Fyderek, Christian Braegger, Simon Travis, Jack Satsangi, Miles Parkes, Nikhil Thapar, Helen Ferry, Julie C. Matte, Kimberly Gilmour, Andrzej Wędrychowicz, Peter Sullivan, Carmel Moore, Jennifer Sambrook, Willem H. Ouwehand, David J. Roberts, John Danesh, Toni A. Baeumler, Tudor A. Fulga, Eli M. Carrami, Ahmed A. Ahmed, Rachel Wilson, Jeffrey C. Barrett, Abdul Elkadri, Anne M. Griffiths, COLORS in IBD group investigators, Marlen Zurek, Caterina Strisciuglio, Mamoun Elawad, Bernice Lo, Oxford IBD cohort study investigators, Carolina V. Arancibia-Cárcamo, Adam Bailey, Ellie Barnes, Elizabeth Bird‐Lieberman, Oliver Brain, Barbara Braden, Jane Collier, James E. East, Lucy Howarth, Satish Keshav, Paul Klenerman, Simon J. Leedham, Rebecca Palmer, Fiona Powrie, Alison Simmons, INTERVAL Study, Matthew R. Walker, Zoe Tolkien, Stephen Kaptoge, David L. Allen, Susan Mehenny, Jonathan Mant, Emanuele Di Angelantonio, Simon G. Thompson, Swiss IBD cohort investigators, Bahtiyar Yılmaz, Pascal Juillerat, Markus B. Geuking, Reiner Wiest, Andrew J. Macpherson, Francisco Bravo, Lukas Brügger, Ove Carstens, Ulrike Graf Bigler, Benjamin Heimgartner, Monica Rusticeanu, Sybille Schmid, Bruno Strebel, Aurora Tatu, Radu Țuțuian, Reiner Wiest, Ove Øyås, Charlotte Ramon, Jörg Stelling, Yannick Franc, Nicolas Fournier, Valérie Pittet, Bernard Burnand, Mara Egger, Yannick Franc, Delphine Golay, Astrid Marot, Leilla Musso, Valérie Pittet, Jean‐Benoît Rossel
Abstract
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 ~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 < 4 × 10 −10 ), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10 −10 ). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.