title: Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease.
abstract: Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.forename: Alan
authors.initials: A
authors.lastname: Huett
authors.forename: Petric
authors.initials: P
authors.lastname: Kuballa
authors.forename: Shannon D
authors.initials: SD
authors.lastname: Chilewski
authors.forename: Aimee
authors.initials: A
authors.lastname: Landry
authors.forename: Philippe
authors.initials: P
authors.lastname: Goyette
authors.forename: Michael C
authors.initials: MC
authors.lastname: Zody
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hall
authors.forename: Steven R
authors.initials: SR
authors.lastname: Brant
authors.forename: Judy H
authors.initials: JH
authors.lastname: Cho
authors.forename: Richard H
authors.initials: RH
authors.lastname: Duerr
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
mesh_terms: D001343:Autophagy / Q000235:genetics; D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion
chemical_list: D019204:GTP-Binding Proteins; C513539:IRGM protein, human