Tuesday, 19 March 2013

23AndMe replicates a common variant association with chordoma

I am quite excited (and frankly a bit relieved) by the fact that 23AndMe replicated a finding which we published last year. In that first study we associated a common coding variant located in the gene brachyury with much increased odds of developing a rare bone cancer called chordoma (odds ratio around 5 which is really unusual for a common variant). This research received support from the Chordoma foundation which also has a report on the first paper.

Why I was worried

This finding was really a bit of a miracle. As a statistician, I am the person supposed to tell clinicians that small underpowered association studies are pointless. This one pushed the limit quite far, with 40 patients in the discovery set. It was even a candidate study because the initial sequencing work only considered the brachyury gene. This gene is a strong candidate for chordoma owing to the role of duplications in familial forms of the disease. When my colleague Nischalan Pillay came to me with these results, I did not believe them at all. It took me a while and several failures at challenging the result to start believing. The addition of exome sequence data helped rule out technical artifacts. But even with the paper accepted, I must say I had doubts. Now it's OK.

What 23AndMe did

23AndMe is in this amazing position where they can gather information a posteriori on rare diseases like chordoma in a very large cohort of patients. They could rapidly put together a panel of 22 cases (and many controls obviously) that confirmed our result. They describe the work in their blog post which is well worth a quick read. I am really excited by the possibilities offerred by the 23AndMe experimental design. There is really much to do with this ressource. It is also a good but somewhat puzzling thought that any association result published can be almost right away challenged and checked by 23AndMe. This reminds me of the ongoing position of Decode which could publish an incredible amount of results by taking advantage of a ressource that no one else could match.

What it means for chordoma research

The finding for the research on chordoma is quite significant. From a heritability point of view, it is obviously a massive chunk explained. A rs2305089-CC individual has almost no chance of developing chordoma, whereas a TT individual has substantially higher risk (about 25 fold compared to CC).  In fact the 23AndMe description is a bit misleading when they state that CC represents the typical odds of developing chordoma: the variant is so common that the heterozygous group is probably a better representation of the typical odds. This being said the disease is still very rare, so even a TT genotype (like me in fact) should not panic. This is still a very unlikely disease to develop.

Now does that lead to a treatment? Far from that, and in fact the effect of that high risk variant may occur early in development and be absolutely impossible to target from a therapeutic point of view. But still, this is a possibility to explore and it is one important piece of the pattern of inheritance of bone cancers.

Update (June 9 2013)
Nick Ericksson from 23AndMe kindly communicated the exact numbers from the replication work.
Genotypes: (AA/AG/GG)
Cases: 12/10/2
Controls: 68/131/41

The 240 controls were chosen to not report any cancer and to provide the best ancestry match for the cases (as determined by the first 5 components of a PCA analysis). A simple Fisher exact test, which in R looks like this:

fisher.test(matrix(nrow = 2, ncol = 2, data = c(12*2 + 10, 10 + 2*2, 68*2 + 131, 131+ 41*2), byrow = TRUE))

yields a two-tailed P-value of 0.047 (and half of that of course to test the exact replication hypothesis of the Nature Genetics paper).  I note that the odds ratio is lower than our estimates (point estimate OR = 2 in this replication set). It may well be that we have a case of "winner's curse" for our Nat Gen paper but only the future will tell.

Very many thanks to Nick Eriksson and the 23andMe team to share these data.