U sing a high-density single nucleotide polymorphism (SNP)-typing platform (Affymetrix 500K, Santa Clara, CA) Parkes et al performed a genome-wide scan of 1748 Crohn's disease (CD) cases and 2938 controls and replicated a selected number of SNPs in independent populations. These scans identified the autophagy gene IRGM as a novel locus in CD susceptibility, 7 other novel loci, as well as replicating many previously published associations.
Initial data from their genome-wide analysis indicated 6 novel strongly CD-associated loci, as well the established susceptibility genes NOD2, IL23R, and ATG16L1. The authors set out to test 37 SNPs from 31 loci (each initially associated to at least P Ο½ 10 Οͺ5 ) in an independent cohort of 1182 European individuals with CD and 5746 controls. This yielded 12 SNPs with significantly differing allele frequencies between CD cases and controls. These 12 markers were subjected to validation in a further 2024 independent population controls and formally tested for CD-association. Of the 12, 4 novel CD-associated loci successfully replicated. Those confirmed included 2 SNPs flanking the IRGM gene on chromosome 5q33.1 (with combined probabilities of P Ο 2.1 Ο« 10 Οͺ10 and P Ο 3.8 Ο« 10 Οͺ9 ), a SNP within the NKX2-3 gene (NK2 transcription factor related, locus 3) on chromosome 10q24.2 (P Ο 3.7 Ο« 10 Οͺ10 ) and a region of high linkage disequilibrium (LD) containing over 20 genes on chromosome 3p21 (P Ο 4.9 Ο« 10 Οͺ8 ). Further analysis of the IRGM locus detected only a silent variant (313TΟΎC) associated with CD, in near-perfect LD with the originally identified SNP. Of an additional 25 loci that did not reach genome-wide significance in the original Wellcome Trust Case Control Consortium (WTCCC) study, 5 showed evidence of association in the replication cohort, including 4 novel loci. These results indicate that many marginally significant loci from whole genome scans may represent true susceptibility alleles.