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In recent years the inflammatory bowel diseases (IBD)—Crohn's disease and ulcerative colitis—have emerged as a model for all complex traits in the successful dissection of the molecular basis of inherited susceptibility by non-parametric linkage analysis1 2 and genome-wide association studies (GWAS).3–5 The recent meta-analyses of GWAS carried out by the International Inflammatory Bowel Disease Genetics Consortium have now reported the identification of 99 susceptibility loci involved in the pathogenesis of Crohn's disease and ulcerative colitis.4 5
These successes in candidate gene discovery have provided new insights into the pathogenetic mechanisms involved in the chronic intestinal inflammation associated with IBD. These data provide strong evidence that Crohn's disease and ulcerative colitis are related complex diseases, sharing some, but not all, susceptibility loci.5 It is clear that while some pathogenic pathways are implicated in both Crohn's disease and ulcerative colitis—notably, interleukin (IL)-23 signalling6 and Th17 cell activation,7 other innate immune mechanisms appear to be implicated in Crohn's disease only (eg, autophagy, and NOD2 signalling). Similarly, aspects of the maintenance of epithelial barrier function are most strongly implicated in ulcerative colitis.8 Furthermore, it is clear that many of the genetic determinants involved in IBD are also implicated in other complex disorders, such as type I diabetes and coeliac disease (in press).9 Both expected and unexpected associations are evident, and have provided avenues for further research.
Along with this exciting progress, however, new challenges have emerged for researchers in this complex field. Of the estimated heritability of IBD, which has been derived from concordance rates in twin pairs, <30% …