title: A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.
abstract: We performed a genome-wide association study of 19,779 nonsynonymous SNPs in 735 individuals with Crohn disease and 368 controls. A total of 7,159 of these SNPs were informative. We followed up on all 72 SNPs with P <or= 0.01 with an allele-based disease association test in 380 independent Crohn disease trios, 498 Crohn disease singleton cases and 1,032 controls. Disease association of rs2241880 in the autophagy-related 16-like 1 gene (ATG16L1) was replicated in these samples (P = 4.0 x 10(-8)) and confirmed in a UK case-control sample (P = 0.0004). By haplotype and regression analysis, we found that marker rs2241880, a coding SNP (T300A), carries virtually all the disease risk exerted by the ATG16L1 locus. The ATG16L1 gene encodes a protein in the autophagosome pathway that processes intracellular bacteria. We found a statistically significant interaction with respect to Crohn disease risk between rs2241880 and the established CARD15 susceptibility variants (P = 0.039). Together with the lack of association between rs2241880 and ulcerative colitis (P > 0.4), these data suggest that the underlying biological process may be specific to Crohn disease.
authors.affiliation: Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. jhampe@1med.uni-kiel.de
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Markus
authors.initials: M
authors.lastname: Teuber
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.forename: Mario
authors.initials: M
authors.lastname: Albrecht
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mayr
authors.forename: Francisco M
authors.initials: FM
authors.lastname: De La Vega
authors.forename: Jason
authors.initials: J
authors.lastname: Briggs
authors.forename: Simone
authors.initials: S
authors.lastname: Günther
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Prescott
authors.forename: Clive M
authors.initials: CM
authors.lastname: Onnie
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Fölsch
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein