Genome-wide Association Scanning Highlights Two Autophagy Genes,ATG16L1 and IRGM,as Being Significantly Associated with Crohn’s Disease

The era of genome-wide association (GWA) scanning has shed new light on the genetic basis of common disease and nowhere is this better illustrated than Crohn’s disease (CD). CD is a chronic debilitating inflammatory bowel disease characterized by stricturing and fistula formation. Mainstays of current therapy are immune suppression and surgery. The pathogenesis of CD is poorly understood, but it has long been recognized that both genetic susceptibility and bacterial antigens play important roles. A variety of intracellular bacteria have been postulated to trigger CD, but the evidence for any one organism is equivocal. The current consensus is that commensal gut bacteria provide the drive for CD-related inflammation. Three GWA scans undertaken in the last 6 months have identified 10 new loci demonstrating highly significant and replicated association with CD. Two of the strongest hits implicate genes IRGM and ATG16L1, which encode proteins thought to be critical to the autophagy pathway. The critical next step is functional characterization of the CD-associated genetic variants in IRGM and ATG16L. It seems highly plausible that variation in these genes holds the key to understanding exactly which bacteria drive the intestinal inflammation of CD and the mechanism by which they do this.

Addendum to:

Sequence Variants in the Autophagy Gene IRGM and Multiple Other Replicating Loci Contribute to Crohn's Disease Susceptibility

M. Parkes, J.C. Barrett, N.J. Prescott, M. Tremelling, C.A. Anderson, S.A. Fisher, R.G. Roberts, E.R. Nimmo, F.R. Cummings, D. Soars, H. Drummond, C.W. Lees, S.A. Khawaja, R. Bagnall, D.A. Burke, C.E. Todhunter, T. Ahmad, C.M. Onnie, W. McArdle, D. Strachan, G. Bethel, C. Bryan, C.M. Lewis, P. Deloukas, A. Forbes, J. Sanderson, D.P. Jewell, J. Satsangi, J.C. Mansfield, Wellcome Trust Case Control Consortium, L. Cardon and C.G. Mathew

Nat Genet 2007; 39:830-2