Tag Archive for 'Crohn’s disease'

Looking closer at natural selection in inflammatory bowel disease

As I mentioned a few weeks ago, we recently published a large study into the genetics of inflammatory bowel disease (IBD), which included a number of analyses digging into the biology and evolutionary history of IBD genetic risk. Gratifyingly, our paper has stimulated a lot of discussion among other scientists, which has generated several ideas about future directions for this work. One question that was raised by several population-genetics experts at ASHG was about our natural selection analysis, and in particular our claim to discover an enrichment of balancing selection in IBD loci. In the paper, we found clear signals of natural selection on IBD loci, a subset of which we interpreted as balancing selection. In this post I will set out how I came to this conclusion, but then outline another explanation that could explain the results: recent local positive selection in Europeans.

Continue reading ‘Looking closer at natural selection in inflammatory bowel disease’

Dozens of new IBD genes, but can they predict disease?

Out in Nature this week is a paper by three Genomes Unzipped authors reporting 71 new genetic associations with inflammatory bowel disease (IBD). This breaks the record for the largest number of associations for any common disease, and includes many new and interesting biological insights that you should all go and read about in the paper itself (pay-to-access I’m afraid) or on the Sanger Institute’s website.

One thing that we did not discuss in the paper was genetic prediction of IBD (i.e. using the risk variants we have discovered to predict who will or will not develop the disease). In this post I want to outline some of the situations in which we have considered using genetic risk prediction of IBD, and discuss whether any of them would actually work in practice.

Continue reading ‘Dozens of new IBD genes, but can they predict disease?’

From GWAS to pathways, the consequences of DTC genetics and screening by sequencing

A paper out in PLoS Genetics this week takes a step towards using genome-wide association data to reconstruct functional pathways. Using protein-protein interaction data and tissue-specific expression data, the authors reconstruct biochemical pathways that underlie various diseases, by looking for variants that interact with genes in GWAS regions. These networks can then tell us about what systems are disrupted by GWAS variants as a whole, as well as identifying potential drug targets. The figure to the right shows the network constructed for Crohn’s disease; large colored circles are genes in GWAS loci, small grey circles are other genes in the network they constructed. As an interesting side note, the GWAS variants were taken from a 2008 study; since then, we have published a new meta-analysis, which implicated a lot of new regions. 10 genes in these regions, marked as small red circles on the figure, were also in the disease network. [LJ]

23andMe customers will be interested in a neat little FireFox plug-in that allows them to view their own genotypes for any 23andMe SNP mentioned on a web page. You can download the plug-in here (you’ll need to have an up-to-date version of FireFox), and I have a brief review of the tool here. [DM]
Continue reading ‘From GWAS to pathways, the consequences of DTC genetics and screening by sequencing’

Solving Medical Mysteries Using Sequencing

There is a real “wow” paper out in pre-print at the journal Genetics in Medicine. It is a wonderful example of the application of cutting edge sequencing technology to solve a medical mystery. Even better, the authors also include an auxiliary discussion about the medical and ethical issues surrounding the diagnosis, which raises some interesting issues about the transition from research to clinical sequencing.

The Case

A child manifested severe inflammation of the bowel at 15 months; antibiotics failed to clear it up, and he started to lose weight. Standard treatments seemed to have only sporadic effects, and only severe treatment with immunosuppressants, surgery and full bowel clearing could slow down the disease, which is not a long term solution. No cause could be found; the patient’s active immune system seemed to be acting abnormally, but all tests for the known congenital immune deficiencies came back negative. The doctors could try a full bone-marrow transplant, but without knowing what was causing the disease, and where it was localised, they had no way of knowing if such an extreme intervention would be successful.

Such a severe and early onset disease is likely to be genetic, but testing immune genes at random to find the mutation could take years before it turned anything up. Meanwhile, the child was seriously malnourished, and at times required daily wound care under general anaesthetic. A few years ago this might have been the end of the story.

Continue reading ‘Solving Medical Mysteries Using Sequencing’

Friday Links

At the risk of turning Friday Links into a self-trumpet-blowing occasion, we are happy to report that a number of GNZ contributors (Jeff, Carl and Luke) are authors on a new Crohn’s disease GWAS meta-analysis of 6000 patients that came out in Nature Genetics this week. The study brings the number of Crohn’s associations up to 71, with 30 novel, bringing the proportion of heritability explained up to about 24%; also worth noting that all of the associations from the previous meta-analysis were replicated it this one, showing how the cross-platform independent replication experiments that are now standard have largely obliterated false positives in GWAS. There were also 5 loci that showed evidence of a second, independent signal, which I think is a promising sign of things to come.

Continue reading ‘Friday Links’

Page optimized by WP Minify WordPress Plugin