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

被引：51

作者：

Serra, Eva Goncalves ^{[1
]}

Schwerd, Tobias ^{[2
,31
]}

Moutsianas, Loukas ^{[1
]}

Cavounidis, Athena ^{[2
]}

Fachal, Laura ^{[1
]}

Pandey, Sumeet ^{[2
]}

Kammermeier, Jochen ^{[3
]}

Croft, Nicholas M. ^{[4
,5
]}

Posovszky, Carsten ^{[6
]}

Rodrigues, Astor ^{[7
]}

Russell, Richard K. ^{[8
]}

Barakat, Farah ^{[4
,5
]}

Auth, Marcus K. H. ^{[9
]}

Heuschkel, Robert ^{[10
]}

Zilbauer, Matthias ^{[10
]}

Fyderek, Krzysztof ^{[11
]}

Braegger, Christian ^{[12
,13
]}

Travis, Simon P. ^{[2
]}

Satsangi, Jack ^{[2
,14
]}

Parkes, Miles ^{[15
]}

Thapar, Nikhil ^{[3
]}

Ferry, Helen ^{[2
]}

Matte, Julie C. ^{[1
]}

Gilmour, Kimberly C. ^{[3
]}

Wedrychowicz, Andrzej ^{[11
]}

Sullivan, Peter ^{[7
]}

Moore, Carmel ^{[16
,17
]}

Sambrook, Jennifer ^{[17
,18
]}

Ouwehand, Willem ^{[1
,16
,17
,18
]}

Roberts, David ^{[16
,19
,20
]}

Danesh, John ^{[1
,17
]}

Baeumler, Toni A. ^{[21
,22
]}

Fulga, Tudor A. ^{[21
,22
]}

Karaminejadranjbar, Mohammad ^{[21
,22
]}

Ahmed, Ahmed ^{[21
,22
,23
]}

Wilson, Rachel ^{[2
]}

Barrett, Jeffrey C. ^{[1
]}

Elkadri, Abdul ^{[24
,25
,26
]}

Griffiths, Anne M. ^{[24
,25
,26
]}

Snapper, Scott B. ^{[27
,28
,29
]}

Shah, Neil ^{[3
]}

Muise, Aleixo M. ^{[24
,25
,26
]}

Wilson, David C. ^{[30
]}

Uhlig, Holm H. ^{[2
,7
]}

Anderson, Carl A. ^{[1
]}

Zurek, Marlen ^{[32
]}

Strisciuglio, Caterina ^{[33
]}

Elawad, Mamoun ^{[34
]}

Lo, Bernice ^{[34
]}

Arancibia-Carcamo, Carolina ^{[2
]}

机构：

[1] Wellcome Sanger Inst, Wellcome Genome Campus, Hinxton, England

[2] Univ Oxford, Translat Gastroenterol Unit, Oxford, England

[3] Great Ormond St Hosp Sick Children, London, England

[4] Queen Mary Univ London, Blizard Inst, Barts & London Sch Med, London, England

[5] Royal London Childrens Hosp, Barts Hlth NHS Trust, London, England

[6] Univ Klinikum, Ulm, Germany

[7] Univ Oxford, Dept Paediat, Oxford, England

[8] Royal Hosp Children, Glasgow, Lanark, Scotland

[9] Alder Hey Childrens Hosp, Liverpool, Merseyside, England

[10] Addenbrookes Hosp, Cambridge, England

[11] Jagiellonian Univ Med Coll, Dept Paediat Gastroenterol & Nutr, Krakow, Poland

[12] Univ Childrens Hosp Zurich, Div Gastroenterol & Nutr, Zurich, Switzerland

[13] Univ Childrens Hosp Zurich, Childrens Res Ctr, Zurich, Switzerland

[14] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[15] Addenbrookes Hosp, Dept Gastroenterol, IBD Res Unit, Cambridge, England

[16] Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England

[17] Univ Cambridge, INTERVAL Coordinating Ctr, Dept Publ Hlth & Primary Care, Cambridge, England

[18] Univ Cambridge, Dept Haematol, Cambridge, England

[19] John Radcliffe Hosp, NHS Blood & Transplant Oxford Ctr, Level 2, Oxford, England

[20] Univ Oxford, John Radcliffe Hosp, Biomed Res Ctr, Oxford Haematol Theme,Radcliffe Dept Med, Oxford, England

[21] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford, England

[22] Univ Oxford, John Radcliffe Hosp, Radcliffe Dept Med, Oxford, England

[23] Univ Oxford, Surg Innovat & Evaluat & Mol Diagnost Themes, Nat Inst Hlth Res Oxford Biomed Res Ctr, Oxford, England

[24] Univ Toronto, Fac Med, Dept Biochem & Pediat, Toronto, ON, Canada

[25] SickKids Inflammatory Bowel Dis Ctr, Toronto, ON, Canada

[26] Hosp Sick Children, Res Inst, Cell Biol Program, Toronto, ON, Canada

[27] Boston Childrens Hosp, Div Gastroenterol Hepatol & Nutr, Boston, MA USA

[28] Harvard Med Sch, Boston, MA USA

[29] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA USA

[30] Univ Edinburgh, Child Life & Hlth, Edinburgh, Midlothian, Scotland

[31] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Pediat, Hauner Childrens Hosp, Munich, Germany

[32] St Georg Hosp, Leipzig, Germany

[33] Univ Naples Federico II, Sect Pediat, Dept Translat Med Sci, Naples, Italy

[34] Sidra Med & Res Ctr, Doha, Qatar

[35] NHS Blood & Transplant, Longley Lane, Sheffield, S Yorkshire, England

[36] Univ Bern, Dept Biomed Res, Maurice Muller Labs, Bern, Switzerland

[37] Univ Bern, Univ Hosp Bern, Dept Visceral Surg & Med, Bern, Switzerland

[38] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Basel, Switzerland

[39] Swiss Fed Inst Technol, SIB Swiss Inst Bioinformat, Basel, Switzerland

[40] Univ Lausanne Hosp, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland

[41] Gastroenterol La Source Beaulieu, Lausanne, Switzerland

[42] CHU Vaudois, Dept Med, Serv Gastroenterol & Hepatol, Lausanne, Switzerland

[43] Univ Lausanne, Lausanne, Switzerland

[44] Univ Bern, Inst Pathol, Div Expt Pathol, Bern, Switzerland

[45] Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Zurich, Switzerland

[46] Clin Montchoisi, Lausanne, Switzerland

[47] Kantonsspital St Gallen, St Gallen, Switzerland

[48] Kantonsspital Luzern, Luzern, Switzerland

[49] Klin Kinder & Jugendliche, Kantonspital Aarau, Aarau, Switzerland

[50] Hop Riviera Site Samaritain, Vevey, Vaud, Switzerland

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

英国医学研究理事会; 英国惠康基金; 瑞士国家科学基金会;

关键词：

CROHNS-DISEASE; MOLECULAR DIAGNOSIS; SEQUENCE VARIANTS; READ ALIGNMENT; MUTATIONS; ASSOCIATION; SUSCEPTIBILITY; LOCI; MANIFESTATIONS; DEFICIENCY;

D O I：

10.1038/s41467-019-14275-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：15

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