Skip to main content
Grant Details

Grant Number: 1R01CA141743-01 Interpret this number
Primary Investigator: Duerr, Richard
Organization: University Of Pittsburgh At Pittsburgh
Project Title: Replication of Association Signals Identified in Ulcerative Colitis Gwas
Fiscal Year: 2009
Back to top


Abstract

DESCRIPTION (provided by applicant): The overall goal of this application is to discover genetic risk loci for ulcerative colitis by attempting to replicate/extend the evidence for association at single nucleotide polymorphisms (SNPs) identified in a metaanalysis of ulcerative colitis genome-wide association studies (GWAS). Ulcerative colitis and Crohn's disease are the two major forms of inflammatory bowel disease. They are thought to result from a dysregulated mucosal immune response triggered by ubiquitous enteric bacteria in genetically susceptible individuals. The two disorders share many characteristics but unique clinical features also distinguish them, suggesting that they share some genetic susceptibility loci but differ at others. Genome-wide significant evidence for 32 Crohn's disease loci was found in a GWAS meta-analysis and replication study. Variants in IL23R and the major histocompatibility complex are associated with both ulcerative colitis and Crohn's disease, but most of the identified Crohn's disease loci show only nominal or no significant evidence for association with ulcerative colitis. The NIDDK Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC) recently completed an ulcerative colitis GWAS using Illumina genotyping beadchip data from 977 cases and 2,122 controls that passed quality control and were matched, by gender and ancestry. The NIDDK IBDGC's ulcerative colitis GWAS and a limited replication study in additional case-control samples, all of European ancestry, identified ulcerative colitis loci on chromosomes 1p36 and 12q15, in addition to IL23R and the major histocompatibility complex. A meta-analysis of the NIDDK IBDGC and two additional ulcerative colitis GWAS datasets, all generated in European ancestry case-control samples using Illumina genotyping beadchips, is underway. The ulcerative colitis GWAS meta-analysis is expected to include post quality control data for approximately 280,000 SNPs in more than 2,600 cases and approximately twice this number of controls. This grant application proposes to attempt to replicate/extend the most promising ulcerative colitis GWAS meta-analysis association signals in additional European ancestry case-control samples from North America, the Netherlands, Germany, Austria and Italy. In addition to genotyping the replication samples at SNPs with promising association evidence in the ulcerative colitis GWAS meta-analysis, ancestry informative markers will also be genotyped so that association analyses can be controlled for population structure. Genotyping technologies and costs are constantly evolving, so it is difficult to predict which genotyping platform will be most cost-effective, how many replication samples can be genotyped, how deep into the ulcerative colitis GWAS meta-analysis hit list the replication analyses can go, and how many ancestry informative markers can be genotyped within budget limitations at the time the proposed study would commence. The tentative plan is to use a 768-plex Illumina GoldenGate assay to genotype more than 500 of the top ulcerative colitis metaanalysis hits plus a set of SNPs that discern ancestry strata within European ancestry samples.

Back to top


Publications

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data.
Authors: Romagnoni A. , Jégou S. , Van Steen K. , Wainrib G. , Hugot J.P. , International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) .
Source: Scientific reports, 2019-07-17; 9(1), p. 10351.
EPub date: 2019-07-17.
PMID: 31316157
Related Citations

Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease and cross-phenotype associations.
Authors: Márquez A. , Kerick M. , Zhernakova A. , Gutierrez-Achury J. , Chen W.M. , Onengut-Gumuscu S. , González-Álvaro I. , Rodriguez-Rodriguez L. , Rios-Fernández R. , González-Gay M.A. , et al. .
Source: Genome medicine, 2018-12-20; 10(1), p. 97.
EPub date: 2018-12-20.
PMID: 30572963
Related Citations

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.
Authors: Momozawa Y. , Dmitrieva J. , Théâtre E. , Deffontaine V. , Rahmouni S. , Charloteaux B. , Crins F. , Docampo E. , Elansary M. , Gori A.S. , et al. .
Source: Nature communications, 2018-06-21; 9(1), p. 2427.
EPub date: 2018-06-21.
PMID: 29930244
Related Citations

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.
Authors: Hinks A. , Marion M.C. , Cobb J. , Comeau M.E. , Sudman M. , Ainsworth H.C. , Bowes J. , Juvenile Idiopathic Arthritis Consortium for Immunochip , Becker M.L. , Bohnsack J.F. , et al. .
Source: Arthritis & rheumatology (Hoboken, N.J.), 2018 06; 70(6), p. 957-962.
EPub date: 2018-04-21.
PMID: 29426059
Related Citations

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease.
Authors: Hui K.Y. , Fernandez-Hernandez H. , Hu J. , Schaffner A. , Pankratz N. , Hsu N.Y. , Chuang L.S. , Carmi S. , Villaverde N. , Li X. , et al. .
Source: Science translational medicine, 2018-01-10; 10(423), .
PMID: 29321258
Related Citations

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.
Authors: Schwerd T. , Bryant R.V. , Pandey S. , Capitani M. , Meran L. , Cazier J.B. , Jung J. , Mondal K. , Parkes M. , Mathew C.G. , et al. .
Source: Mucosal immunology, 2018 03; 11(2), p. 562-574.
EPub date: 2017-11-01.
PMID: 29091079
Related Citations

Fine-mapping inflammatory bowel disease loci to single-variant resolution.
Authors: Huang H. , Fang M. , Jostins L. , Umićević Mirkov M. , Boucher G. , Anderson C.A. , Andersen V. , Cleynen I. , Cortes A. , Crins F. , et al. .
Source: Nature, 2017-07-13; 547(7662), p. 173-178.
EPub date: 2017-06-28.
PMID: 28658209
Related Citations

A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition.
Authors: Li D. , Achkar J.P. , Haritunians T. , Jacobs J.P. , Hui K.Y. , D'Amato M. , Brand S. , Radford-Smith G. , Halfvarson J. , Niess J.H. , et al. .
Source: Gastroenterology, 2016 10; 151(4), p. 724-32.
EPub date: 2016-08-01.
PMID: 27492617
Related Citations

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.
Authors: Cleynen I. , Boucher G. , Jostins L. , Schumm L.P. , Zeissig S. , Ahmad T. , Andersen V. , Andrews J.M. , Annese V. , Brand S. , et al. .
Source: Lancet (London, England), 2016-01-09; 387(10014), p. 156-67.
EPub date: 2015-10-18.
PMID: 26490195
Related Citations

Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls.
Authors: Fortune M.D. , Guo H. , Burren O. , Schofield E. , Walker N.M. , Ban M. , Sawcer S.J. , Bowes J. , Worthington J. , Barton A. , et al. .
Source: Nature genetics, 2015 Jul; 47(7), p. 839-46.
EPub date: 2015-06-08.
PMID: 26053495
Related Citations

High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.
Authors: Goyette P. , Boucher G. , Mallon D. , Ellinghaus E. , Jostins L. , Huang H. , Ripke S. , Gusareva E.S. , Annese V. , Hauser S.L. , et al. .
Source: Nature genetics, 2015 Feb; 47(2), p. 172-9.
EPub date: 2015-01-05.
PMID: 25559196
Related Citations

Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies.
Authors: Ellinghaus D. , Zhang H. , Zeissig S. , Lipinski S. , Till A. , Jiang T. , Stade B. , Bromberg Y. , Ellinghaus E. , Keller A. , et al. .
Source: Gastroenterology, 2013 Aug; 145(2), p. 339-47.
EPub date: 2013-04-25.
PMID: 23624108
Related Citations

High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.
Authors: Ellinghaus D. , Baurecht H. , Esparza-Gordillo J. , Rodríguez E. , Matanovic A. , Marenholz I. , Hübner N. , Schaarschmidt H. , Novak N. , Michel S. , et al. .
Source: Nature genetics, 2013 Jul; 45(7), p. 808-12.
EPub date: 2013-06-02.
PMID: 23727859
Related Citations

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.
Authors: Liu J.Z. , Hov J.R. , Folseraas T. , Ellinghaus E. , Rushbrook S.M. , Doncheva N.T. , Andreassen O.A. , Weersma R.K. , Weismüller T.J. , Eksteen B. , et al. .
Source: Nature genetics, 2013 Jun; 45(6), p. 670-5.
EPub date: 2013-04-21.
PMID: 23603763
Related Citations

Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.
Authors: Beaudoin M. , Goyette P. , Boucher G. , Lo K.S. , Rivas M.A. , Stevens C. , Alikashani A. , Ladouceur M. , Ellinghaus D. , Törkvist L. , et al. .
Source: PLoS genetics, 2013; 9(9), p. e1003723.
EPub date: 2013-09-12.
PMID: 24068945
Related Citations

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
Authors: Jostins L. , Ripke S. , Weersma R.K. , Duerr R.H. , McGovern D.P. , Hui K.Y. , Lee J.C. , Schumm L.P. , Sharma Y. , Anderson C.A. , et al. .
Source: Nature, 2012-11-01; 491(7422), p. 119-24.
PMID: 23128233
Related Citations

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.
Authors: Trynka G. , Hunt K.A. , Bockett N.A. , Romanos J. , Mistry V. , Szperl A. , Bakker S.F. , Bardella M.T. , Bhaw-Rosun L. , Castillejo G. , et al. .
Source: Nature genetics, 2011-11-06; 43(12), p. 1193-201.
EPub date: 2011-11-06.
PMID: 22057235
Related Citations




Back to Top