title: Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4.
abstract: 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 x 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.
authors: Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
authors: Cécile
authors: C
authors: Libioulle
authors: Edouard
authors: E
authors: Louis
authors: Sarah
authors: S
authors: Hansoul
authors: Cynthia
authors: C
authors: Sandor
authors: Frédéric
authors: F
authors: Farnir
authors: Denis
authors: D
authors: Franchimont
authors: Séverine
authors: S
authors: Vermeire
authors: Olivier
authors: O
authors: Dewit
authors: Martine
authors: M
authors: de Vos
authors: Anna
authors: A
authors: Dixon
authors: Bruno
authors: B
authors: Demarche
authors: Ivo
authors: I
authors: Gut
authors: Simon
authors: S
authors: Heath
authors: Mario
authors: M
authors: Foglio
authors: Liming
authors: L
authors: Liang
authors: Debby
authors: D
authors: Laukens
authors: Myriam
authors: M
authors: Mni
authors: Diana
authors: D
authors: Zelenika
authors: André
authors: A
authors: Van Gossum
authors: Paul
authors: P
authors: Rutgeerts
authors: Jacques
authors: J
authors: Belaiche
authors: Mark
authors: M
authors: Lathrop
authors: Michel
authors: M
authors: Georges
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D018078:Receptors, Prostaglandin E / Q000235:genetics*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012689:Sequence Homology, Nucleic Acid
chemical_list: C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype