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

COLORS in IBD group investigators; Oxford IBD cohort study investigators; INTERVAL Study; Swiss IBD cohort investigators; UK Inflammatory Bowel Disease (IBD) Genetics Consortium; NIDDK IBD Genetics Consortium; Eva Gonçalves 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 K. H. Auth; Robert Heuschkel; Matthias Zilbauer; Krzysztof Fyderek; Christian Braegger; Simon P. Travis; Jack Satsangi; Miles Parkes; Nikhil Thapar; Helen Ferry; Julie C. Matte; Kimberly C. Gilmour; Andrzej Wedrychowicz; Peter Sullivan; Carmel Moore; Jennifer Sambrook; Willem Ouwehand; David Roberts; John Danesh; Toni A. Baeumler; Tudor A. Fulga; Eli M. Carrami; Ahmed Ahmed; Rachel Wilson; Jeffrey C. Barrett; Abdul Elkadri; Anne M Griffiths; Scott B Snapper; Neil Shah; Aleixo M. Muise; David C Wilson; Holm Uhlig; Carl A Anderson; William Newman

doi:10.1038/s41467-019-14275-y

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

COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK Inflammatory Bowel Disease (IBD) Genetics Consortium, NIDDK IBD Genetics Consortium, Eva Gonçalves 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 K. H. Auth, Robert HeuschkelMatthias Zilbauer, Krzysztof Fyderek, Christian Braegger, Simon P. Travis, Jack Satsangi, Miles Parkes, Nikhil Thapar, Helen Ferry, Julie C. Matte, Kimberly C. Gilmour, Andrzej Wedrychowicz, Peter Sullivan, Carmel Moore, Jennifer Sambrook, Willem Ouwehand, David Roberts, John Danesh, Toni A. Baeumler, Tudor A. Fulga, Eli M. Carrami, Ahmed Ahmed, Rachel Wilson, Jeffrey C. Barrett, Abdul Elkadri, Anne M Griffiths, Scott B Snapper, Neil Shah, Aleixo M. Muise, David C Wilson, Holm Uhlig, Carl A Anderson, William Newman

Division of Evolution, Infection and Genomics

Research output: Contribution to journal › Article › peer-review

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

Original language	English
Article number	995
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-019-14275-y
Publication status	Published - 21 Feb 2020

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COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK Inflammatory Bowel Disease (IBD) Genetics Consortium, NIDDK IBD Genetics Consortium, Gonçalves Serra, E., Schwerd, T., Moutsianas, L., Cavounidis, A., Fachal, L., Pandey, S., Kammermeier, J., Croft, N. M., Posovszky, C., Rodrigues, A., Russell, R. K., Barakat, F., Auth, M. K. H., ... Newman, W. (2020). Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nature Communications, 11, 1-15. Article 995. https://doi.org/10.1038/s41467-019-14275-y

@article{31eaeef5325f46389ed2fabe9b360943,

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

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

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

year = "2020",

month = feb,

day = "21",

doi = "10.1038/s41467-019-14275-y",

language = "English",

volume = "11",

pages = "1--15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer Nature",

}

COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK Inflammatory Bowel Disease (IBD) Genetics Consortium, NIDDK IBD Genetics Consortium, Gonçalves Serra, E, Schwerd, T, Moutsianas, L, Cavounidis, A, Fachal, L, Pandey, S, Kammermeier, J, Croft, NM, Posovszky, C, Rodrigues, A, Russell, RK, Barakat, F, Auth, MKH, Heuschkel, R, Zilbauer, M, Fyderek, K, Braegger, C, Travis, SP, Satsangi, J, Parkes, M, Thapar, N, Ferry, H, Matte, JC, Gilmour, KC, Wedrychowicz, A, Sullivan, P, Moore, C, Sambrook, J, Ouwehand, W, Roberts, D, Danesh, J, Baeumler, TA, Fulga, TA, Carrami, EM, Ahmed, A, Wilson, R, Barrett, JC, Elkadri, A, Griffiths, AM, Snapper, SB, Shah, N, Muise, AM, Wilson, DC, Uhlig, H, Anderson, CA & Newman, W 2020, 'Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease', Nature Communications, vol. 11, 995, pp. 1-15. https://doi.org/10.1038/s41467-019-14275-y

TY - JOUR

T1 - Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

AU - COLORS in IBD group investigators

AU - Oxford IBD cohort study investigators

AU - INTERVAL Study

AU - Swiss IBD cohort investigators

AU - UK Inflammatory Bowel Disease (IBD) Genetics Consortium

AU - NIDDK IBD Genetics Consortium

AU - Gonçalves Serra, Eva

AU - Schwerd, Tobias

AU - Moutsianas, Loukas

AU - Cavounidis, Athena

AU - Fachal, Laura

AU - Pandey, Sumeet

AU - Kammermeier, Jochen

AU - Croft, Nicholas M.

AU - Posovszky, Carsten

AU - Rodrigues, Astor

AU - Russell, Richard K

AU - Barakat, Farah

AU - Auth, Marcus K. H.

AU - Heuschkel, Robert

AU - Zilbauer, Matthias

AU - Fyderek, Krzysztof

AU - Braegger, Christian

AU - Travis, Simon P.

AU - Satsangi, Jack

AU - Parkes, Miles

AU - Thapar, Nikhil

AU - Ferry, Helen

AU - Matte, Julie C.

AU - Gilmour, Kimberly C.

AU - Wedrychowicz, Andrzej

AU - Sullivan, Peter

AU - Moore, Carmel

AU - Sambrook, Jennifer

AU - Ouwehand, Willem

AU - Roberts, David

AU - Danesh, John

AU - Baeumler, Toni A.

AU - Fulga, Tudor A.

AU - Carrami, Eli M.

AU - Ahmed, Ahmed

AU - Wilson, Rachel

AU - Barrett, Jeffrey C.

AU - Elkadri, Abdul

AU - Griffiths, Anne M

AU - Snapper, Scott B

AU - Shah, Neil

AU - Muise, Aleixo M.

AU - Wilson, David C

AU - Uhlig, Holm

AU - Anderson, Carl A

AU - Newman, William

PY - 2020/2/21

Y1 - 2020/2/21

N2 - 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 -10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P -10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis.

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

UR - https://europepmc.org/articles/PMC7035382

U2 - 10.1038/s41467-019-14275-y

DO - 10.1038/s41467-019-14275-y

M3 - Article

C2 - 32081864

SN - 2041-1723

VL - 11

SP - 1

EP - 15

JO - Nature Communications

JF - Nature Communications

M1 - 995

ER -

COLORS in IBD group investigators, Oxford IBD cohort study investigators, INTERVAL Study, Swiss IBD cohort investigators, UK Inflammatory Bowel Disease (IBD) Genetics Consortium, NIDDK IBD Genetics Consortium et al. Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease. Nature Communications. 2020 Feb 21;11:1-15. 995. doi: 10.1038/s41467-019-14275-y

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

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