Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4

By C. Libioulle, E. Louis, S. Hansoul, C. Sandor, F. Farnir, D. Franchimont, Severine Vermeire, O. Dewit, M. De Vos, A. Dixon and 13 more. PLoS Genetics, 2007

609 citations recorded by the source corpus.

To identify novel susceptibility loci for Crohn disease (CD), we undertook a genome-wide association study with more than 300,000 SNPs characterized in 547 patients and 928 controls. We found three chromosome regions that provided evidence of disease association with p-values between 10−6 and 10−9. Two of these (IL23R on Chromosome 1 and CARD15 on Chromosome 16) correspond to genes previously reported to be associated with CD. In addition, a 250-kb region of Chromosome 5p13.1 was found to contain multiple markers with strongly suggestive evidence of disease association (including four markers with p < 10−7). We replicated the results for 5p13.1 by studying 1,266 additional CD patients, 559 additional controls, and 428 trios. Significant evidence of association (p < 4 × 10−4) was found in case/control comparisons with the replication data, while associated alleles were over-transmitted to affected offspring (p < 0.05), thus confirming that the 5p13.1 locus contributes to CD susceptibility. The CD-associated 250-kb region was saturated with 111 SNP markers. Haplotype analysis supports a complex locus architecture with multiple variants contributing to disease susceptibility. The novel 5p13.1 CD locus is contained within a 1.25-Mb gene desert. We present evidence that disease-associated alleles correlate with quantitative expression levels of the prostaglandin receptor EP4, PTGER4, the gene that resides closest to the associated region. Our results identify a major new susceptibility locus for CD, and suggest that genetic variants associated with disease risk at this locus could modulate cis-acting regulatory elements of PTGER4.

Subfields: Genetics, Immunology, Surgery

View Paper: https://www.semanticscholar.org/paper/e3d7dee3f2ac44d5122032f2d5763602fadad9ac

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Citations in the corpus

New IBD genetics: common pathways with other diseases (2011, background): “25 Mb gene desert, but eQTL analysis suggests that the adjacent PTGER4 gene is responsible.(118) SNPs in linkage disequilibrium with those associated with Crohn’s disease are associated with ulcerative colitis,(28) and also appear to confer susceptibility to MS, but presently fall just short of geno”
A genome-wide association study of global gene expression (2007, methodology): “Our database has also been of use in the identification of a new susceptibility locus from Crohn's disease on chromosome 5 (ref”
XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease (2008, neutral): “Cell 134, 743–756, September 5, 2008 ª2008 Elsevier Inc. 751”
The Genetic Signatures of Noncoding RNAs (2009, background): “, [146]), and while it is conceivable that they affect distal enhancers (see, e.”
Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility (2011, background): “SNPs in or near CARD9 and PTGER4 (encoding prostaglandin E receptor 4, EP4 subtype) have also been associated with Crohn's disease previousl”
STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement (2009, neutral): “org 0158 February 2009 | Volume 6 | Issue 2 | e1000022 association studies [85,87–105].”
NeST, a long noncoding RNA, controls microbial susceptibility and epigenetic activation of the Ifng locus (2013, neutral): “Many genome-wide association studies have also pointed to intergenic regions as heritable causes of human disease (Libioulle et al., 2007; Sotelo et al., 2010).”