Tag Archive for 'ulcerative colitis'

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.

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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.

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At odds with disease risk estimates

It's all a game of Risk!

The first thing I did when I received my genotyping results from 23andMe was log on to their website and take a look at my estimated disease risks. For most people, these estimates are one of the primary reasons for buying a direct to consumer (DTC) genetics kit. But how accurate are these disease risk estimates? How robust is the information that goes into calculating them? In a previous post I focused on how odds ratios (the ratio of the odds of disease if allele A is carried as opposed to allele B) can vary across different populations, environments and age groups and, as a consequence, affect disease risk estimates.  It turns out that even if we forget about these concerns for a moment, getting an accurate estimate of disease risk is far from straightforward. One of the primary challenges is deciding which disease loci to include in the risk prediction and in this post I will investigate the effect this decision can have on risk estimates.

To help me in my quest, I will use ulcerative colitis (UC) as an example throughout the post, estimating Genomes Unzipped members’ risk for the disease as I go. Ulcerative colitis is one of two common forms of autoimmune infllammatory bowel disease and I have selected it not on the basis of any special properties (either genetic or biological) but because I am familiar with the genetics of the disease having worked on it extensively.

The table below gives our ulcerative colitis risks according to 23andMe. The numbers in the table represent the percentage of people 23andMe would expect to suffer from UC given our genotype data (after taking our sex and ethnicity into account). The colours highlight individuals who fall into 23andMe’s “increased risk” (red) or “decreased risk” (blue) categories based on comparisons with the average risk (males: 0.77%; females 0.51%). As far as I am aware none of us actually do suffer from UC.
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Ulcerative colitis genetics, Nature on the human genome

Yes, it’s Friday Links time yet again here at Genomes Unzipped.

A paper in Nature Genetics this week reports the results of a large meta-analysis of GWAS studies into ulcerative colitis, which more than doubles the number of loci known for the disease from 18 to 47. This pushes the proportion of heritability explained from 11 to 16%, and sheds more light on the shared and non-shared pathways between ulcerative colitis and Crohn’s disease, along with the interplay with other immune and inflammatory disorders.

The lead author is a Genomes Unzipped contributor, but he emphatically refused to contribute to this Friday Links post, on the grounds that he doesn’t want to blow his own trumpet. So, instead, here is a quote from the Sanger Institute’s press release:

“The genomic regions we have identified give us an insight into the biology underlying ulcerative colitis,” says Dr Carl Anderson, from the Wellcome Trust Sanger Institute and first author on the paper. “These important initial discoveries are the building blocks on which we can begin to derive better IBD treatments, though much further work is needed before these become a clinical reality.” [LJ]

Nature has a special issue this week devoted to the decade of progress since the publication of the human genome sequence. Eric Lander, who was first author on the original Human Genome Project paper, has a long and thoughtful commentary on the subsequent impact of that publication across a wide range of fields. Elaine Mardis accompanies Lander’s piece with a discussion of the astonishing advances in sequencing technology over the last decade (including a figure that emphasises the tremendous impact of the development of the Solexa/Illumina Genome Analyzer platform, which boosted sequencing capacity by eight orders of magnitude in a single year!).

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