Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci

Abstract

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.

Fig. 1.

Overview of GWA study, fine-mapping, and replication studies in regions on chromosomes 1p31.3, 4p16.1, and 3p21.31. A shows the results of the GWA analysis for three regions (1p31.3, 700 kb; 4p16.1, 600 kb; and 3p21.31, 1.2 Mb). Plots indicate the nominal −log₁₀ P values for haplotypes corresponding to five (green), seven (red), and nine (orange) consecutive marker windows. B shows the FM results for the QFP, C shows the FM results for the German trios, and D shows the FM results for the German cases/controls. Regions sequenced in the 1p31.3 and 4p16.1 regions are shown as a blue bar. E shows the LD structure in controls from the QFP based on the D′ algorithm as implemented in Haploview 3.32 (36).