title: Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease.
abstract: 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. 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 x 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.
authors.affiliation: Whitehead Institute/Massachusetts Institute of Technology, Center for Genome Research, Cambridge, Massachusetts, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Rioux
authors.forename: M J
authors.initials: MJ
authors.lastname: Daly
authors.forename: M S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: K
authors.initials: K
authors.lastname: Lindblad
authors.forename: H
authors.initials: H
authors.lastname: Steinhart
authors.forename: Z
authors.initials: Z
authors.lastname: Cohen
authors.forename: T
authors.initials: T
authors.lastname: Delmonte
authors.forename: K
authors.initials: K
authors.lastname: Kocher
authors.forename: K
authors.initials: K
authors.lastname: Miller
authors.forename: S
authors.initials: S
authors.lastname: Guschwan
authors.forename: E J
authors.initials: EJ
authors.lastname: Kulbokas
authors.forename: S
authors.initials: S
authors.lastname: O'Leary
authors.forename: E
authors.initials: E
authors.lastname: Winchester
authors.forename: K
authors.initials: K
authors.lastname: Dewar
authors.forename: T
authors.initials: T
authors.lastname: Green
authors.forename: V
authors.initials: V
authors.lastname: Stone
authors.forename: C
authors.initials: C
authors.lastname: Chow
authors.forename: A
authors.initials: A
authors.lastname: Cohen
authors.forename: D
authors.initials: D
authors.lastname: Langelier
authors.forename: G
authors.initials: G
authors.lastname: Lapointe
authors.forename: D
authors.initials: D
authors.lastname: Gaudet
authors.forename: J
authors.initials: J
authors.lastname: Faith
authors.forename: N
authors.initials: N
authors.lastname: Branco
authors.forename: S B
authors.initials: SB
authors.lastname: Bull
authors.forename: R S
authors.initials: RS
authors.lastname: McLeod
authors.forename: A M
authors.initials: AM
authors.lastname: Griffiths
authors.forename: A
authors.initials: A
authors.lastname: Bitton
authors.forename: G R
authors.initials: GR
authors.lastname: Greenberg
authors.forename: E S
authors.initials: ES
authors.lastname: Lander
authors.forename: K A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: T J
authors.initials: TJ
authors.lastname: Hudson
mesh_terms: D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D003424:Crohn Disease / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide
chemical_list: D016207:Cytokines