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

• Published in: Nature genetics Vol. 29; no. 2; pp. 223 - 228
• Main Authors: Rioux, John D., Daly, Mark J., Silverberg, Mark S., Lindblad, Kerstin, Steinhart, Hillary, Cohen, Zane, Delmonte, Terrye, Kocher, Kerry, Miller, Katie, Guschwan, Sheila, Kulbokas, Edward J., O'Leary, Sinead, Winchester, Ellen, Dewar, Ken, Green, Todd, Stone, Valerie, Chow, Christine, Cohen, Albert, Langelier, Diane, Lapointe, Gilles, Gaudet, Daniel, Faith, Janet, Branco, Nancy, Bull, Shelley B., McLeod, Robin S., Griffiths, Anne M., Bitton, Alain, Greenberg, Gordon R., Lander, Eric S., Siminovitch, Katherine A., Hudson, Thomas J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2001; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; chromosome 5; Chromosome Mapping; Chromosomes, Human, Pair 5; Crohn Disease - genetics; Crohn's disease; Cytokines; Cytokines - genetics; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genes. Genome; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic susceptibility; Genetic variance; Genetic Variation; Genetics; Genomes; Haplotypes; Health aspects; Human Genetics; Humans; IBD5 gene; Inflammatory bowel disease; letter; Linkage Disequilibrium; Localization; Molecular and cellular biology; Molecular genetics; Multigene Family; Mutation; Polymorphism, Single Nucleotide; Publishing; Canada; United States > US; Massachusetts; Quebec Canada; Genetic mapping; Gene cluster; Crohn disease; Cytokine; Variations; Digestive diseases; Intestinal disease; Genetics; Inflammatory disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng1001-223

Linkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied 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 susceptibility to Crohn disease. The key issues are: (i) to detect a significant LD signal (ii) to rigorously bound the critical region and (iii) to identify the causal genetic variant within this region. We previously mapped the IBD5 locus to a large region spanning 18 cM of chromosome 5q31 ( P <10 −4 ). Using dense genetic maps of microsatellite markers and single-nucleotide polymorphisms (SNPs) across the entire region, we found strong evidence of LD. We bound the region to a common haplotype spanning 250 kb that shows strong association with the disease ( P <2×10 −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 disease. However, genetic evidence alone is not sufficient to identify the causal mutation within this region, as strong LD across the region results in multiple SNPs having equivalent genetic evidence—each consistent with the expected properties of the IBD5 locus. These results have important implications for Crohn disease in particular and LD mapping in general.