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

Publication

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

Journal Paper/Review - Feb 21, 2020

Anderson Carl A, Barrett Jeffrey C, Wilson Rachel, Ahmed Ahmed, Karaminejadranjbar Mohammad, Fulga Tudor A, Baeumler Toni A, Danesh John, Roberts David, Ouwehand Willem, Sambrook Jennifer, Elkadri Abdul, Griffiths Anne M, COLORS in IBD group investigators, Uhlig Holm H, Wilson David C, Muise Aleixo M, Shah Neil, Snapper Scott B, NIDDK IBD Genetics Consortium, UK IBD Genetics Consortium, Swiss IBD Cohort Investigators, INTERVAL Study, Oxford IBD cohort study investigators, Moore Carmel, Sullivan Peter, Wedrychowicz Andrzej, Russell Richard K, Rodrigues Astor, Posovszky Carsten, Croft Nicholas M, Kammermeier Jochen, Pandey Sumeet, Fachal Laura, Cavounidis Athena, Moutsianas Loukas, Schwerd Tobias, Barakat Farah, Auth Marcus K H, Heuschkel Robert, Gilmour Kimberly C, Matte Julie C, Ferry Helen, Thapar Nikhil, Parkes Miles, Satsangi Jack, Travis Simon P, Braegger Christian, Fyderek Krzysztof, Zilbauer Matthias, Serra Eva Gonçalves

PubMed

32081864

Doi

10.1038/s41467-019-14275-y

Citation

Anderson C, Barrett J, Wilson R, Ahmed A, Karaminejadranjbar M, Fulga T, Baeumler T, Danesh J, Roberts D, Ouwehand W, Sambrook J, Elkadri A, Griffiths A, COLORS in IBD group investigators, Uhlig H, Wilson D, Muise A, Shah N, Snapper S, NIDDK IBD Genetics Consortium, UK IBD Genetics Consortium, Swiss IBD Cohort Investigators, INTERVAL Study, Oxford IBD cohort study investigators, Moore C, Sullivan P, Wedrychowicz A, Russell R, Rodrigues A, Posovszky C, Croft N, Kammermeier J, Pandey S, Fachal L, Cavounidis A, Moutsianas L, Schwerd T, Barakat F, Auth M, Heuschkel R, Gilmour K, Matte J, Ferry H, Thapar N, Parkes M, Satsangi J, Travis S, Braegger C, Fyderek K, Zilbauer M, Serra E. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nat Commun 2020; 11:995.

Type

Journal Paper/Review (English)

Journal

Nat Commun 2020; 11

Publication Date

Feb 21, 2020

Issn Electronic

2041-1723

Pages

995

Brief description/objective

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), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.