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

Authors :
UCL - SSS/IREC/MONT - Pôle Mont Godinne
UCL - (MGD) Service de gastro-entérologie
Serra, Eva Gonçalves
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
COLORS in IBD group investigators
Oxford IBD cohort study investigators
INTERVAL Study
Swiss IBD cohort investigators
UK IBD Genetics Consortium
NIDDK IBD Genetics Consortium
Snapper, Scott B
Shah, Neil
Muise, Aleixo M
Wilson, David C
Uhlig, Holm H
Anderson, Carl A
Marot, Astrid
UCL - SSS/IREC/MONT - Pôle Mont Godinne
UCL - (MGD) Service de gastro-entérologie
Serra, Eva Gonçalves
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
COLORS in IBD group investigators
Oxford IBD cohort study investigators
INTERVAL Study
Swiss IBD cohort investigators
UK IBD Genetics Consortium
NIDDK IBD Genetics Consortium
Snapper, Scott B
Shah, Neil
Muise, Aleixo M
Wilson, David C
Uhlig, Holm H
Anderson, Carl A
Marot, Astrid
Source :
Nature communications, Vol. 11, no. 1, p. 995 (2020)
Publication Year :
2020

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), 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.

Details

Database :
OAIster
Journal :
Nature communications, Vol. 11, no. 1, p. 995 (2020)
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1288275785
Document Type :
Electronic Resource