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

The International IBD Genetics Consortium

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Resumé

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 ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼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.

OriginalsprogEngelsk
Artikelnummer2427
TidsskriftNature Communications
Vol/bind9
Antal sider18
ISSN2041-1723
DOI
StatusUdgivet - 21. jun. 2018

Fingeraftryk

loci
Inflammatory Bowel Diseases
genes
Genes
modules
Genome-Wide Association Study
Transcriptome
Crohn Disease
Causality
Sample Size
Tissue
cells

Citer dette

@article{5457470817ac45679dd99a1daedecfbf,
title = "IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes",
abstract = "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 ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼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.",
keywords = "Adult, Aged, Aged, 80 and over, Cohort Studies, Crohn Disease/genetics, Female, Gene Expression Profiling, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Inflammatory Bowel Diseases/genetics, Male, Middle Aged, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sequence Analysis, DNA",
author = "Yukihide Momozawa and Julia Dmitrieva and Emilie Th{\'e}{\^a}tre and Val{\'e}rie Deffontaine and Souad Rahmouni and Beno{\^i}t Charloteaux and Fran{\cc}ois Crins and Elisa Docampo and Mahmoud Elansary and Gori, {Ann Stephan} and Christelle Lecut and Rob Mariman and Myriam Mni and C{\'e}cile Oury and Ilya Altukhov and Dmitry Alexeev and Yuri Aulchenko and Leila Amininejad and Gerd Bouma and Frank Hoentjen and Mark L{\"o}wenberg and Bas Oldenburg and Pierik, {Marieke J.} and {Vander Meulen-De Jong}, {Andrea E.} and {Van Der Woude}, {C. Janneke} and Visschedijk, {Marijn C.} and Mark Lathrop and Hugot, {Jean Pierre} and Weersma, {Rinse K.} and {De Vos}, Martine and Denis Franchimont and Severine Vermeire and Michiaki Kubo and Edouard Louis and Michel Georges and Clara Abraham and Achkar, {Jean Paul} and Tariq Ahmad and Ananthakrishnan, {Ashwin N.} and Vibeke Andersen and Anderson, {Carl A.} and Andrews, {Jane M.} and Vito Annese and Guy Aumais and Leonard Baidoo and Baldassano, {Robert N.} and Bampton, {Peter A.} and Murray Barclay and Barrett, {Jeffrey C.} and David Ellinghaus and {The International IBD Genetics Consortium}",
year = "2018",
month = "6",
day = "21",
doi = "10.1038/s41467-018-04365-8",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. / The International IBD Genetics Consortium.

I: Nature Communications, Bind 9, 2427, 21.06.2018.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

AU - Momozawa, Yukihide

AU - Dmitrieva, Julia

AU - Théâtre, Emilie

AU - Deffontaine, Valérie

AU - Rahmouni, Souad

AU - Charloteaux, Benoît

AU - Crins, François

AU - Docampo, Elisa

AU - Elansary, Mahmoud

AU - Gori, Ann Stephan

AU - Lecut, Christelle

AU - Mariman, Rob

AU - Mni, Myriam

AU - Oury, Cécile

AU - Altukhov, Ilya

AU - Alexeev, Dmitry

AU - Aulchenko, Yuri

AU - Amininejad, Leila

AU - Bouma, Gerd

AU - Hoentjen, Frank

AU - Löwenberg, Mark

AU - Oldenburg, Bas

AU - Pierik, Marieke J.

AU - Vander Meulen-De Jong, Andrea E.

AU - Van Der Woude, C. Janneke

AU - Visschedijk, Marijn C.

AU - Lathrop, Mark

AU - Hugot, Jean Pierre

AU - Weersma, Rinse K.

AU - De Vos, Martine

AU - Franchimont, Denis

AU - Vermeire, Severine

AU - Kubo, Michiaki

AU - Louis, Edouard

AU - Georges, Michel

AU - Abraham, Clara

AU - Achkar, Jean Paul

AU - Ahmad, Tariq

AU - Ananthakrishnan, Ashwin N.

AU - Andersen, Vibeke

AU - Anderson, Carl A.

AU - Andrews, Jane M.

AU - Annese, Vito

AU - Aumais, Guy

AU - Baidoo, Leonard

AU - Baldassano, Robert N.

AU - Bampton, Peter A.

AU - Barclay, Murray

AU - Barrett, Jeffrey C.

AU - Ellinghaus, David

AU - The International IBD Genetics Consortium

PY - 2018/6/21

Y1 - 2018/6/21

N2 - 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 ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼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.

AB - 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 ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Cohort Studies

KW - Crohn Disease/genetics

KW - Female

KW - Gene Expression Profiling

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Inflammatory Bowel Diseases/genetics

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Sequence Analysis, DNA

U2 - 10.1038/s41467-018-04365-8

DO - 10.1038/s41467-018-04365-8

M3 - Journal article

C2 - 29930244

AN - SCOPUS:85048925642

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 2427

ER -