Genome-Wide Association Study Signal At The 12q12 Locus For Crohn'S Disease May Represent Associations With The Muc19 Gene

Background:Genome-wide association studies (GWAS) in Crohn's disease (CD) have identified associations with single-nucleotide polymorphism (SNP) rs11175593 at chromosome 12q12. The MUC19 and LRRK2 genes reside close to the GWAS signal, but it is as yet unclear which of the 2 genes represent the CD susceptibility genes.Methods:We studied associations between nonsynonymous coding variants in the MUC19 (5) and LRRK2 (3) genes in a case-control sample comprising CD cases aged <18 years at diagnosis. The GWAS lead SNP rs11175593 was also investigated. Allelic, genotype, and haplotype associations were examined assuming different models of inheritance.Results:A total of 530 cases and 600 controls were studied. The mean (SD) age at diagnosis was 12.4 (+/- 3.3). Most cases were male (57.4%). Most patients had ileocolonic disease location (48.8%) and inflammatory behavior at diagnosis (87.0%). Three MUC19 SNPs were nominally significantly associated with CD (rs11564245, AspHis: P = 0.02; rs4768261, SerPhe: P = 0.0008; and rs2933353, GluAla: P = 0.01). Associations with rs4768261 were maintained after corrections for multiple comparisons (permuted, P = 0.007). None of the LRRK2 SNPs were associated with CD. Haplotype analysis supported the single SNP associations noted with the MUC19 gene.Conclusions:GWAS signal at chromosome 12q12 for CD may represent associations with the MUC19 gene.