Integrated genomics of crohn's disease risk variant identifies a role for CLEC12A in antibacterial autophagy

Begun, Jakob, Lassen, Kara G., Jijon, Humberto B., Baxt, Leigh A., Goel, Gautam, Heath, Robert J., Ng, Aylwin, Tam, Jenny M., Kuo, Szu-Yu, Villablanca, Eduardo J., Fagbami, Lola, Oosting, Marije, Kumar, Vinod, Schenone, Monica, Carr, Steven A., Joosten, Leo A. B., Vyas, Jatin M., Daly, Mark J., Netea, Mihai G., Brown, Gordon D., Wijmenga, Cisca and Xavier, Ramnik J. (2015) Integrated genomics of crohn's disease risk variant identifies a role for CLEC12A in antibacterial autophagy. Cell Reports, 11 12: 1905-1918. doi:10.1016/j.celrep.2015.05.045


Author Begun, Jakob
Lassen, Kara G.
Jijon, Humberto B.
Baxt, Leigh A.
Goel, Gautam
Heath, Robert J.
Ng, Aylwin
Tam, Jenny M.
Kuo, Szu-Yu
Villablanca, Eduardo J.
Fagbami, Lola
Oosting, Marije
Kumar, Vinod
Schenone, Monica
Carr, Steven A.
Joosten, Leo A. B.
Vyas, Jatin M.
Daly, Mark J.
Netea, Mihai G.
Brown, Gordon D.
Wijmenga, Cisca
Xavier, Ramnik J.
Title Integrated genomics of crohn's disease risk variant identifies a role for CLEC12A in antibacterial autophagy
Journal name Cell Reports   Check publisher's open access policy
ISSN 2211-1247
Publication date 2015-06-30
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.celrep.2015.05.045
Open Access Status DOI
Volume 11
Issue 12
Start page 1905
End page 1918
Total pages 14
Place of publication New York, NY, United States
Publisher Elsevier
Collection year 2016
Language eng
Formatted abstract
The polymorphism ATG16L1 T300A, associated with increased risk of Crohn's disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1 *300A risk allele. Clec12a-/- mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways invivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease. Although genome-wide association studies are valuable in identifying disease-associated loci, they produce only a partial view of pathogenesis. Using integrated, systems-level approaches to pinpoint genes that interact with the Crohn's-disease-associated variant ATG16L1 T300A, Begun etal. identify CLEC12A as an innate defense gene that functions in antibacterial autophagy.
Keyword Genetic disease
Perturbational profiling
Genomewide association studies (GWASs)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Official 2016 Collection
 
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