Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4.
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.
Libioulle
Cécile
C
Unit of Animal Genomics, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
Louis
Edouard
E
Hansoul
Sarah
S
Sandor
Cynthia
C
Farnir
Frédéric
F
Franchimont
Denis
D
Vermeire
Séverine
S
Dewit
Olivier
O
de Vos
Martine
M
Dixon
Anna
A
Demarche
Bruno
B
Gut
Ivo
I
Heath
Simon
S
Foglio
Mario
M
Liang
Liming
L
Laukens
Debby
D
Mni
Myriam
M
Zelenika
Diana
D
Van Gossum
André
A
Rutgeerts
Paul
P
Belaiche
Jacques
J
Lathrop
Mark
M
Georges
Michel
M
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
C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype