A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1.
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.
Hampe
Jochen
J
Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, University Hospital Schleswig-Holstein, 24105 Kiel, Germany. jhampe@1med.uni-kiel.de
Franke
Andre
A
Rosenstiel
Philip
P
Till
Andreas
A
Teuber
Markus
M
Huse
Klaus
K
Albrecht
Mario
M
Mayr
Gabriele
G
De La Vega
Francisco M
FM
Briggs
Jason
J
Günther
Simone
S
Prescott
Natalie J
NJ
Onnie
Clive M
CM
Häsler
Robert
R
Sipos
Bence
B
Fölsch
Ulrich R
UR
Lengauer
Thomas
T
Platzer
Matthias
M
Mathew
Christopher G
CG
Krawczak
Michael
M
Schreiber
Stefan
S
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
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein