Genes for Crohn's identified

“The number of genes linked to the bowel condition Crohn's disease has been trebled by research that provides promising targets for better therapies,” The Times reported. The newspaper said that the discovery of 21 new genes raises to 32 the number of “DNA passages known to raise susceptibility to the condition”. The newspaper quoted a leading member of the study team as saying that the more we understand about the underlying biology of these diseases, the better equipped we will be to treat them.

The study behind this story provides good evidence that there are a large number of genes that can increase a person’s susceptibility to Crohn’s disease. It should be pointed out that Crohn’s is a complex disorder, and both genetic and environmental factors play a part. More research is needed before these findings can be applied to diagnosis or treatment.

Where did the story come from?

Dr Jeffrey C. Barrett from the Wellcome Trust Centre for Human Genetics at Oxford University and several colleagues from the UK, Europe, Canada and the USA contributed to the research. The study was a joint effort of the Wellcome Trust Case Control Consortium, the NIDDK IBD Genetics Consortium and the French-Belgian IBD Consortium. It was funded by the Medical Research Council and The Wellcome Trust. Individual contributors have support from a variety of sources including the National Institutes of Health, Burroughs Wellcome Foundation and others. The study was published in the peer-reviewed medical journal Nature Genetics .

What kind of scientific study was this?

In this publication, the researchers carried out a meta-analysis of three previously published genome-wide association studies, which looked for particular genetic sequences (variants) that are associated with Crohn’s disease. By pooling the studies, 3,320 people with Crohn’s disease (the cases) and 4,829 controls were available for analysis.

The genetic sequences of these individuals were analysed in an attempt to identify variations that were more common in people with Crohn’s disease. By pooling the studies together, the researchers could identify genetic sequences that were more common in people with Crohn's that the individual studies did not have the power to identify. The variations the researchers looked at were scattered throughout the genetic sequence, and do not all lie within genes or themselves alter the function of genes.

To confirm their results, the researchers performed a further analysis in a separate sample of 2,325 Crohn’s cases and 1,809 controls and 1,339 trios of parents and offspring with Crohn’s disease. In this analysis, they looked to see whether the particular gene sequences they had identified were associated with Crohn’s in the new groups of people.

The researchers then calculated the contribution of the variants to the risk of disease. They also looked at which genes lay near the variants identified, and whether their variants were close (“linked”) to any variants within the genes themselves, using a database of common genetic variants in humans (the HapMap).

What were the results of the study?

The researchers identified 526 distinct genetic sequences in 74 different areas that were much more common in people with Crohn’s disease. Of these 74 areas, 11 have previously been associated with Crohn’s disease in other studies, so their study was essentially investigating the association with 63 newly identified regions.

When the researchers repeated their analysis, they found that 21 of these new regions were significantly associated with the disease in both their initial combined population and the population in their replication study. Overall, they estimated that the 21 newly identified regions and the 11 known regions contribute about 10% of the variation in risk of developing Crohn’s disease. The remaining 90% of risk is due to other genetic factors (estimated to be 40%) and environmental factors (estimated to be 50%).

What interpretations did the researchers draw from these results?

The researchers conclude that their study has identified variations within 21 regions in the genetic sequence that are associated with an increased risk of Crohn’s disease. However, only a small amount of variation in risk is explained by these regions, suggesting that there are still unidentified regions associated with the disease.

What does the NHS Knowledge Service make of this study?

This well-conducted study combined the results of other studies using recognised methods in this field. The researchers raise the following points:

• They say that the validity of combining data from different populations of similar genetic backgrounds (in this case people of European descent) to investigate the association between common genetic variation and disease has yet to be confirmed. As with all genome-wide association studies, power (i.e. having a large enough sample to detect differences within it if they exist) is an important issue. Combining samples from separate studies is a way to increase power. The effects that this pooling will have on the findings is unclear.
• The researchers identified 21 new regions that are strongly associated with Crohn’s disease. They conclude that these combined regions contribute to only about 10% of the overall variance in disease risk demonstrates how complex these disorders can be. They also conclude that it is “plausible that there are still more [variants] to be found”.
• The variants identified in this study may not be the variants that actually increase risk of Crohn’s disease; they may simply lie near to the “causal” variants. More research will be needed to identify these causal variants.

An understanding of the genetics behind Crohn’s will contribute to better detection and possibly treatment, though for now such applications are some way off.

Sir Muir Gray adds...

This should help improve drug treatment.