Replication of Association Signals Identified in Ulcerative Colitis GWAS

Summary

Principal Investigator: Richard Duerr
Abstract: 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.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
    Luke Jostins
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK
    Nature 491:119-24. 2012
  2. pmc Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
    David Ellinghaus
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
    Gastroenterology 145:339-47. 2013
  3. pmc High-density genotyping study identifies four new susceptibility loci for atopic dermatitis
    David Ellinghaus
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
    Nat Genet 45:808-12. 2013
  4. pmc Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease
    Gosia Trynka
    Genetics Department, University Medical Center and University of Groningen, The Netherlands
    Nat Genet 43:1193-201. 2011

Scientific Experts

  • David Ellinghaus
  • Richard H Duerr
  • Stephan Brand
  • Carsten Buning
  • Juliane Winkelmann
  • Jurgen Glas
  • Stefan Schreiber
  • Andre Franke
  • Cisca Wijmenga
  • Thomas Illig
  • Markus M Nothen
  • Bernhard O Boehm
  • Anna Latiano
  • Cyriel Y Ponsioen
  • Rinse K Weersma
  • Severine Vermeire
  • Vibeke Andersen
  • Miles Parkes
  • Vito Annese
  • Limas Kupcinskas
  • Sebastian Zeissig
  • Mark J Daly
  • Christopher G Mathew
  • Mauro D'Amato
  • Jeremy D Sanderson
  • Miquel Sans
  • Tom H Karlsen
  • Luke Jostins
  • Mitja Mitrovič
  • Jeffrey C Barrett
  • Karin Fransen
  • Gosia Trynka
  • Stephan Weidinger
  • Gabriele Mayr
  • Michiaki Kubo
  • Ulf Meyer-Hoffert
  • Sen Yang
  • Atsushi Takahashi
  • Anja Matanovic
  • Tomomitsu Hirota
  • Robert Häsler
  • Andreas Keller
  • Susanna Nikolaus
  • Mario Albrecht
  • Björn Stade
  • Xianbo Zuo
  • Manuel A Rivas
  • Heidi Schaarschmidt
  • Maeve A McAleer
  • James Lee
  • W H Irwin McLean
  • Mayumi Tamari
  • Norbert Hubner
  • Manfred Kayser
  • Holger Prokisch
  • Young Ae Lee
  • Hansjörg Baurecht
  • Nadezhda T Doncheva
  • Andreas Till
  • Ingo Marenholz
  • David P Strachan
  • Jun Wang
  • Elke Rodriguez
  • Katharina Heim
  • Jurgita Skieceviciene
  • Carlo R Berzuini
  • Michael Forster
  • Paul Rutgeerts
  • Regina Fölster-Holst
  • Melanie Hotze
  • Simone Lipinski
  • Lam C Tsoi
  • Yana Bromberg
  • Jane Goodall
  • Liangdan Sun
  • Wendy L McArdle
  • Christian Herder
  • Hu Zhang
  • Philip Stuart
  • Xiao Liu
  • Fuman Jiang
  • Sven Michel
  • Sara Brown
  • Tao Jiang
  • Jorge Esparza-Gordillo
  • Laura Maintz
  • Eva Ellinghaus
  • Xuejun Zhang
  • Alan D Irvine
  • Jonas Halfvarson

Detail Information

Publications4

  1. pmc Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
    Luke Jostins
    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK
    Nature 491:119-24. 2012
    ..Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD...
  2. pmc Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
    David Ellinghaus
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
    Gastroenterology 145:339-47. 2013
    ..We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies...
  3. pmc High-density genotyping study identifies four new susceptibility loci for atopic dermatitis
    David Ellinghaus
    Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
    Nat Genet 45:808-12. 2013
    ..This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis. ..
  4. pmc Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease
    Gosia Trynka
    Genetics Department, University Medical Center and University of Groningen, The Netherlands
    Nat Genet 43:1193-201. 2011
    ..Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease...