Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease.
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.
McCarroll
Steven A
SA
Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Huett
Alan
A
Kuballa
Petric
P
Chilewski
Shannon D
SD
Landry
Aimee
A
Goyette
Philippe
P
Zody
Michael C
MC
Hall
Jennifer L
JL
Brant
Steven R
SR
Cho
Judy H
JH
Duerr
Richard H
RH
Silverberg
Mark S
MS
Taylor
Kent D
KD
Rioux
John D
JD
Altshuler
David
D
Daly
Mark J
MJ
Xavier
Ramnik J
RJ
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
D019204:GTP-Binding Proteins; C513539:IRGM protein, human