Nature Genetics
29, 223 - 228 (2001)
doi:10.1038/ng1001-223
Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn diseaseJohn D. Rioux1, Mark J. Daly1, Mark S. Silverberg2, 3, Kerstin Lindblad1, Hillary Steinhart2, Zane Cohen4, Terrye Delmonte1, Kerry Kocher1, Katie Miller1, Sheila Guschwan1, Edward J. Kulbokas1, Sinead O'Leary1, Ellen Winchester1, Ken Dewar1, Todd Green1, Valerie Stone1, Christine Chow1, Albert Cohen7, Diane Langelier8, Gilles Lapointe9, Daniel Gaudet9, Janet Faith7, Nancy Branco7, Shelley B. Bull6, Robin S. McLeod4, Anne M. Griffiths5, Alain Bitton7, Gordon R. Greenberg2, Eric S. Lander1, 10, 11, Katherine A. Siminovitch2, 3, 11
& Thomas J. Hudson1, 7, 111
Whitehead Institute/Massachusetts Institute of Technology, Center for Genome Research, Cambridge, Massachusetts, USA. 2
Department of Medicine, University of Toronto and the Mount Sinai Hospital Lunenfeld Research Institute and the Hospital for Sick Children, Toronto, Ontario, Canada. 3
Department of Immunology and Medical Genetics, University of Toronto and the Mount Sinai Hospital Lunenfeld Research Institute and the Hospital for Sick Children, Toronto, Ontario, Canada. 4
Department of Surgery, University of Toronto and the Mount Sinai Hospital Lunenfeld Research Institute and the Hospital for Sick Children, Toronto, Ontario, Canada. 5
Department of Pediatrics, University of Toronto and the Mount Sinai Hospital Lunenfeld Research Institute and the Hospital for Sick Children, Toronto, Ontario, Canada. 6
Department of Public Health Sciences, University of Toronto and the Mount Sinai Hospital Lunenfeld Research Institute and the Hospital for Sick Children, Toronto, Ontario, Canada. 7
Department of Gastroenterology and Montreal Genome Center, McGill University Health Center, McGill University, Montréal, Québec, Canada. 8
Centre Hospitalier de Sherbrooke, Sherbrooke, Quebec, Canada. 9
Centre Hospitalier de la Sagamie, Chicoutimi, Quebec, Canada. 10
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 11
These authors co-directed the project.
Correspondence should be addressed to John D. Rioux rioux@genome.wi.mit.edu or Katherine A. Siminovitch ksiminovitch@mtsinai.on.ca or Thomas J. Hudson tjhudson@med.mcgill.ca or Eric S. Lander lander@wi.mit.eduLinkage disequilibrium (LD) mapping provides a powerful method for fine-structure localization of rare disease genes, but has not yet been widely applied to common disease1. 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.
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