TY - JOUR
T1 - IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
AU - Momozawa, Yukihide
AU - Dmitrieva, Julia
AU - Theatre, Emilie
AU - Deffontaine, Valerie
AU - Rahmouni, Souad
AU - Charloteaux, Benoit
AU - Crins, Francois
AU - Docampo, Elisa
AU - Elansary, Mahmoud
AU - Gori, Ann-Stephan
AU - Lecut, Christelle
AU - Mariman, Rob
AU - Mni, Myriam
AU - Oury, Cecile
AU - Altukhov, Ilya
AU - Alexeev, Dmitry
AU - Aulchenko, Yuri
AU - Amininejad, Leila
AU - Bouma, Gerd
AU - Hoentjen, Frank
AU - Lowenberg, 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 - Brand, Stephan
AU - De Jong, Dirk
AU - Zhang, Hu
AU - Int 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 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.
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 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.
KW - INFLAMMATORY-BOWEL-DISEASE
KW - GENOME-WIDE ASSOCIATION
KW - QUANTITATIVE TRAIT LOCUS
KW - RARE VARIANTS
KW - LOW-FREQUENCY
KW - CODING VARIANTS
KW - SEQUENCING DATA
KW - CROHNS-DISEASE
KW - COMPLEX TRAITS
KW - SUSCEPTIBILITY
KW - Humans
KW - Middle Aged
KW - Male
KW - Gene Expression Profiling
KW - Multifactorial Inheritance
KW - Aged, 80 and over
KW - Adult
KW - Female
KW - Crohn Disease/genetics
KW - Genetic Predisposition to Disease
KW - Genetic Association Studies
KW - Genotype
KW - Sequence Analysis, DNA
KW - Aged
KW - Polymorphism, Single Nucleotide
KW - Quantitative Trait Loci
KW - Cohort Studies
KW - Inflammatory Bowel Diseases/genetics
U2 - 10.1038/s41467-018-04365-8
DO - 10.1038/s41467-018-04365-8
M3 - Article
C2 - 29930244
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
M1 - 2427
ER -