Through follow-up of discoveries from the recent CD meta-analysis, this study identifies 4 new susceptibility loci for UC. In addition, we provide replicated association and thereby confirmation of 3 recently reported UC loci. These results therefore add significantly to the body of evidence for shared pathways between the 2 diseases, an observation of considerable importance both in understanding diseases pathogenesis and in discovering new therapeutic targets.
Choice of appropriate statistical thresholds for significance in association studies is important in understanding the validity of the findings. The field now recognizes the need for stringent thresholds to distinguish true signals from false-positive findings. In the current study, we only tested loci showing confirmed or nominal association with CD, for which the prior probability of association with UC is significantly elevated. Accounting for the 29 independent loci tested, Bonferroni correction suggests that P < .0017 is appropriate. Of note, all the new UC loci that we identify meet this criterion by at least an order of magnitude.
The strongest association in this study was with 2 SNPs in tight linkage disequilibrium on chromosome 1q32, establishing this association in UC unequivocally for the first time. Following up WTCCC hits in CD, Franke et al14
had previously found some evidence for association between this locus and UC, but at P
= .0017 this was of borderline significance given the 50 loci tested. Three genes map to the 170-kilobase region (as defined by HapMap recombination hot spots) highlighted by the association signal. These are C1orf106, KIF21B
, and CACNA1S
. Fine mapping is required to identify which gene is relevant to UC (and indeed CD) pathogenesis.
One of the strongest new signals was observed at a locus encoding Janus kinase 2 (JAK2
) on chromosome 9p24. In addition, we confirmed association between UC and signal transducer and activator of transcription 3 (STAT3
) as recently reported by Franke et al.14
These findings thus confirm that the JAK-STAT
pathway is a common feature of both UC and CD pathogenesis. This is a focal point in the downstream transmission of signals from cell surface receptors to the nucleus to modify transcription of various genes. Several cytokines and other immunoactive molecules utilize this signal transduction pathway. These include interferons, epidermal growth factor, IL-5, IL-6, and notably also the IL12/23 axis within which variants are also associated in common with both UC and CD.10,13
play a key role in IL23R
signaling, and STAT3
is critical for maturation of naïve CD4+ve T cells to the proinflammatory Th17 cells increasingly recognized as central to driving inflammation in IBD.
The genes highlighted by the 2 other novel UC association signals are currently poorly characterized. LYRM4
) on chromosome 6p25 codes for a mitochondrial ribosomal protein with sequence homology to NADH
on chromosome 6p22 is noteworthy for being recently confirmed as a type 2 diabetes susceptibility gene.24
Our study provides the first independent replication of association between UC and variants in IL18RAP
. The IL-18 receptor accessory protein (IL18RAP
) is involved in IL-18 signaling and has sequence homology to the IL-1 receptor accessory protein (IL1RACP
). IL-18 is released by macrophages and, with IL-12, induces cell-mediated immunity following microbial infection.25-27
As well as association with CD, variants in IL18RAP
have also been reported to be associated with celiac disease.22,28
(Cyclin fold protein-1) has also previously shown association with both CD and UC. The protein product belongs to the cyclin protein superfamily and contains a protein-binding domain that plays a role in cell-cycle and transcription control by regulating cyclin-dependent kinases.
None of the UC loci that we have identified showed significant subphenotype association. With regard to disease extent, this is perhaps unsurprising given that these are all also CD susceptibility loci. As generic IBD loci, it would be surprising if any were associated with one subclass of UC as defined by extent of colonic involvement but not others. Such subphenotype specific loci are more likely to be associated with UC alone and to derive from forthcoming GWAS studies in UC, although a surprising feature has been the paucity of such effects in CD.10
We do not see significant evidence of association at the previously reported UC susceptibility locus, HERC2
= .085), even though our power to detect association at rs916977 given the reported UC effect size (OR, 1.46) is estimated to be 100% (assuming a multiplicative disease model, a population prevalence of 0.0024,21
and a falsepositive rate [α
] of .0017). The minor allele frequency in the Franke et al 2008 population controls is 0.106, yet, in our combined controls, the frequency is 0.140 (similar to the case frequencies of both studies). The minor allele frequency of this SNP in the CEU HapMap B36 data is 0.133. It appears that the unusually low minor allele frequency at this SNP in the control samples from the Franke et al 2008 study underlies the unreplicated association at this locus. Additional, high-powered, case-control, and family-based association studies are therefore needed to elucidate fully the role of HERC2
A number of loci previously associated with CD did not show evidence of association with UC. For some loci, this may reflect a lack of power because extremely large sample sets would be required to reliably detect small effects with ORs <1.15. For others, our UC sample set had good or high power to detect an effect comparable with that seen in CD (). Of note, such loci include those encoding genes ICOSLG and CCR6. Both encode proteins that appear to play a key role in T-cell activation and differentiation. Therefore, it appears that CD-specific risk loci are not limited to disruption of innate immune pathways such as autophagy and NOD2.
We compared effect sizes for the shared UC/CD loci but did not observe any evidence of significant heterogeneity (Cochrane Q test: P < .05). Although there is some uncertainty in these effect size estimates, we can rule out scenarios in which any of these loci has a substantially different effect in UC vs CD. Overall, both phenotypes conform to the expectation of many genes of modest effect.
was not associated with CD in the current study. We had 100% power to detect association at this SNP (assuming a multiplicative allelic OR of 1.23, a population prevalence of 0.00145,21
= .05). Even allowing for a much reduced OR of 1.10, our power to detect association to this SNP is 82%. It therefore appears that variants within ECM1
specifically confer susceptibility to UC risk.
What are the implications of this study with regard to the overall genetic architecture of the IBDs and the molecular relationship between CD and UC? Clearly, a complete understanding must await full, well-powered GWAS experiments in UC to compare with the GWAS studies in CD. In the meantime, interrogation of CD GWAS hits in our UC panel has identified a number of shared loci but has also found some key differences. Of the shared pathways, the Th17 inflammatory axis is particularly noteworthy and highlighted by the fact that a number of its molecular components show association with susceptibility to CD and UC. This is in the context of earlier reports highlighting innate immunity pathways of NOD2 and autophagy as specific to CD and the current study suggesting that ECM1 is UC specific. The precise causal variants of the 9 loci shared between UC and CD have not yet been defined, and their functional significance remains to be elucidated. These are immediate priorities in the fast moving field of IBD genetics, and their resolution should further illuminate both the underlying mechanisms of chronic intestinal inflammation and the cellular processes that lead to the distinct phenotypes of CD and UC.