IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

被引：149

作者：

Momozawa, Yukihide ^{[1
,2
,3
]}

Dmitrieva, Julia ^{[1
,2
]}

Theatre, Emilie ^{[1
,2
]}

Deffontaine, Valerie ^{[1
,2
]}

Rahmouni, Souad ^{[1
,2
]}

Charloteaux, Benoit ^{[1
,2
]}

Crins, Francois ^{[1
,2
]}

Docampo, Elisa ^{[1
,2
]}

Elansary, Mahmoud ^{[1
,2
]}

Gori, Ann-Stephan ^{[1
,2
]}

Lecut, Christelle ^{[4
]}

Mariman, Rob ^{[1
,2
]}

Mni, Myriam ^{[1
,2
]}

Oury, Cecile ^{[4
]}

Altukhov, Ilya ^{[5
]}

Alexeev, Dmitry ^{[6
]}

Aulchenko, Yuri ^{[7
,8
,9
]}

Amininejad, Leila ^{[10
]}

Bouma, Gerd ^{[11
]}

Hoentjen, Frank ^{[12
]}

Lowenberg, Mark ^{[13
]}

Oldenburg, Bas ^{[14
]}

Pierik, Marieke J. ^{[15
]}

vander Meulen-de Jong, Andrea E. ^{[16
]}

van der Woude, C. Janneke ^{[17
]}

Visschedijk, Marijn C. ^{[18
,19
]}

Lathrop, Mark ^{[20
]}

Hugot, Jean-Pierre ^{[21
]}

Weersma, Rinse K. ^{[18
,19
]}

De Vos, Martine ^{[22
]}

Franchimont, Denis ^{[10
]}

Vermeire, Severine ^{[23
]}

Kubo, Michiaki ^{[3
]}

Louis, Edouard ^{[24
,25
,26
]}

Georges, Michel ^{[1
,2
]}

Abraham, Clara ^{[27
]}

Achkar, Jean-Paul ^{[28
,29
]}

Ahmad, Tariq ^{[30
]}

Ananthakrishnan, Ashwin N. ^{[31
,32
]}

Andersen, Vibeke ^{[33
,34
,35
]}

Anderson, Carl A. ^{[36
]}

Andrews, Jane M. ^{[37
]}

Annese, Vito ^{[38
,39
]}

Aumais, Guy ^{[40
,41
]}

Baidoo, Leonard ^{[42
]}

Baldassano, Robert N. ^{[43
]}

Bampton, Peter A. ^{[44
,45
]}

Barclay, Murray ^{[46
]}

Barrett, Jeffrey C. ^{[36
]}

Bayless, Theodore M. ^{[47
]}

机构：

[1] Univ Liege B34, GIGA R, Unit Anim Genom, WELBIO, 1 Ave Hop, B-4000 Liege, Belgium

[2] Univ Liege B34, Fac Vet Med, 1 Ave Hop, B-4000 Liege, Belgium

[3] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan

[4] Univ Liege B34, Lab Thrombosis & Hemostasis, GIGA R, 1 Ave Hop, B-4000 Liege, Belgium

[5] Moscow Inst Phys & Technol, Inst Skiy Pereulok 9, Dolgoprudnyi 141700, Russia

[6] Novosibirsk State Univ, Pirogova Ave 2, Novosibirsk 630090, Russia

[7] PolyOmics, Het Vlaggeschip 61, NL-5237 PA sHertogenbosch, Netherlands

[8] SD RAS, Inst Cytol & Genet, Lavrentyeva Ave 10, Novosibirsk 630090, Russia

[9] Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland

[10] Univ Libre Bruxelles, Fac Med, Gastroenterol Med, Route Lennik 808, B-1070 Anderlecht, Belgium

[11] Vrije Univ Amsterdam Med Ctr, Dept Gastroenterol & Hepatol, NL-1081 HV Amsterdam, Netherlands

[12] Radboud Univ Nijmegen Med Ctr, Dept Gastroenterol & Hepatol, NL-6525 GA Nijmegen, Netherlands

[13] Amsterdam Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

[14] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, NL-3584 CX Utrecht, Netherlands

[15] Univ Med Ctr Maastricht, Dept Gastroenterol & Hepatol, NL-6229 HX Maastricht, Netherlands

[16] Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, NL-2333 ZA Leiden, Netherlands

[17] Erasmus MC, Dept Gastroenterol & Hepatol, NL-3015 CE Rotterdam, Netherlands

[18] Univ Groningen, Dept Gastroenterol & Hepatol, Hanzepl 1, NL-9713 GZ Groningen 1, Netherlands

[19] Univ Med Ctr Groningen, Hanzepl 1, NL-9713 GZ Groningen 1, Netherlands

[20] McGill Univ, Ctr Mol & Computat Genom, 740 Dr Penfield Ave, Montreal, PQ H3A 0G1, Canada

[21] Univ Paris Diderot, AP HP, Sorbonne Paris Cite, UMR INSERM 1149, 48 Bd Serurier, F-75019 Paris, France

[22] Univ Hosp, Dept Gastroenterol, De Pintelaan 185, B-9000 Ghent, Belgium

[23] Katholieke Univ Leuven, Dept Clin & Expt Med, Translat Res Gastrointestinal Disorders, UZ Herestr 49, B-3000 Leuven, Belgium

[24] Univ Liege, CHU Liege, 1 Ave Hop, B-4000 Liege, Belgium

[25] Univ Liege, Unit Gastroenterol, GIGA R, 1 Ave Hop, B-4000 Liege, Belgium

[26] Univ Liege, Fac Med, 1 Ave Hop, B-4000 Liege, Belgium

[27] Yale Sch Med, Dept Internal Med, Sect Digest Dis, New Haven, CT USA

[28] Cleveland Clin, Digest Dis Inst, Dept Gastroenterol & Hepatol, Cleveland, OH 44106 USA

[29] Cleveland Clin, Dept Pathobiol, Lerner Res Inst, Cleveland, OH 44106 USA

[30] Peninsula Coll Med & Dent, Exeter, Devon, England

[31] Harvard Med Sch, Massachusetts Gen Hosp, Gastroenterol Unit, Boston, MA 02114 USA

[32] Harvard Med Sch, Div Med Sci, Boston, MA USA

[33] Hosp Southern Jutland, IRS Ctr Sonderjylland, Focused Res Unit Mol Diagnost & Clin Res MOK, DK-6200 Abenra, Denmark

[34] Univ Southern Denmark, Inst Mol Med, DK-5000 Odense, Denmark

[35] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark

[36] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Hinxton CB10 1SA, Cambs, England

[37] Royal Adelaide Hosp, Dept Gastroenterol & Hepatol, Inflammatory Bowel Dis Serv, Adelaide, SA, Australia

[38] IRCCS CSS, Unit Gastroenterol, San Giovanni Rotondo, Italy

[39] Azienda Osped Univ AOU Careggi, SOD, Gastroenterol 2, Florence, Italy

[40] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada

[41] Hop Maison Neuve Rosemont, Dept Gastroenterol, Montreal, PQ, Canada

[42] Univ Pittsburgh, Sch Med, Div Gastroenterol Hepatol & Nutr, Dept Med, Pittsburgh, PA 15213 USA

[43] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[44] Flinders Univ S Australia, Flinders Med Ctr, Dept Gastroenterol & Hepatol, Adelaide, SA, Australia

[45] Flinders Univ S Australia, Sch Med, Adelaide, SA, Australia

[46] Univ Otago, Dept Med, Christchurch, New Zealand

[47] Johns Hopkins Univ, Sch Med, Dept Med, Meyerhoff Inflammatory Bowel Dis Ctr, Baltimore, MD 21205 USA

[48] Univ Kiel, Dept Gen Internal Med, Kiel, Germany

[49] Royal Victoria Hosp, Div Gastroenterol, Montreal, PQ, Canada

[50] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

欧盟地平线“2020”;

关键词：

INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION; QUANTITATIVE TRAIT LOCUS; RARE VARIANTS; LOW-FREQUENCY; CODING VARIANTS; SEQUENCING DATA; CROHNS-DISEASE; COMPLEX TRAITS; SUSCEPTIBILITY;

D O I：

10.1038/s41467-018-04365-8

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：

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by similar to 9720 regulatory modules, of which similar to 3000 operate in multiple tissues and similar to 970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that >= 10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

引用

页数：18

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