Genetic variation in the 5q31 cytokine gene cluster confers susceptibilityto Crohn disease

Linkage disequilibrium (LD) mapping provides a powerful method for fine-str ucture localization of rare disease genes, but has not yet been widely appl ied to common disease(1). We sought to design a systematic approach for LD mapping and apply it to the localization of a gene (IBD5) conferring suscep tibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identif y the causal genetic variant within this region. We previously mapped the I BD5 locus to a large region spanning 18 cM of chromosome 5q31 (P<10(-4)). U sing dense genetic maps of microsatellite markers and single-nucleotide pol ymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows stron g association with the disease (P<2x10(-7)) and contains the cytokine gene cluster, This finding provides overwhelming evidence that a specific common haplotype of the cytokine region in 5q31 confers susceptibility to Crohn d isease. However, genetic evidence alone is not sufficient to identify the c ausal mutation within this region, as strong LD across the region results i n multiple SNPs having equivalent genetic evidence-each consistent with the expected properties of the 1BD5 locus. These results have important implic ations for Crohn disease in particular and LID mapping in general.