Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.
We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
Rioux
John D
JD
Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada. rioux@broad.mit.edu
Xavier
Ramnik J
RJ
Taylor
Kent D
KD
Silverberg
Mark S
MS
Goyette
Philippe
P
Huett
Alan
A
Green
Todd
T
Kuballa
Petric
P
Barmada
M Michael
MM
Datta
Lisa Wu
LW
Shugart
Yin Yao
YY
Griffiths
Anne M
AM
Targan
Stephan R
SR
Ippoliti
Andrew F
AF
Bernard
Edmond-Jean
EJ
Mei
Ling
L
Nicolae
Dan L
DL
Regueiro
Miguel
M
Schumm
L Philip
LP
Steinhart
A Hillary
AH
Rotter
Jerome I
JI
Duerr
Richard H
RH
Cho
Judy H
JH
Daly
Mark J
MJ
Brant
Steven R
SR
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology*; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics; D009656:North America; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors; D019255:NADPH Oxidases; C113333:NCF4 protein, human