title: Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.
abstract: 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.
authors: Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada. rioux@broad.mit.edu
authors: John D
authors: JD
authors: Rioux
authors: Ramnik J
authors: RJ
authors: Xavier
authors: Kent D
authors: KD
authors: Taylor
authors: Mark S
authors: MS
authors: Silverberg
authors: Philippe
authors: P
authors: Goyette
authors: Alan
authors: A
authors: Huett
authors: Todd
authors: T
authors: Green
authors: Petric
authors: P
authors: Kuballa
authors: M Michael
authors: MM
authors: Barmada
authors: Lisa Wu
authors: LW
authors: Datta
authors: Yin Yao
authors: YY
authors: Shugart
authors: Anne M
authors: AM
authors: Griffiths
authors: Stephan R
authors: SR
authors: Targan
authors: Andrew F
authors: AF
authors: Ippoliti
authors: Edmond-Jean
authors: EJ
authors: Bernard
authors: Ling
authors: L
authors: Mei
authors: Dan L
authors: DL
authors: Nicolae
authors: Miguel
authors: M
authors: Regueiro
authors: L Philip
authors: LP
authors: Schumm
authors: A Hillary
authors: AH
authors: Steinhart
authors: Jerome I
authors: JI
authors: Rotter
authors: Richard H
authors: RH
authors: Duerr
authors: Judy H
authors: JH
authors: Cho
authors: Mark J
authors: MJ
authors: Daly
authors: Steven R
authors: SR
authors: Brant
mesh_terms: 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
chemical_list: 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