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The importance of rare variants in common diseases

In a couple recent posts (and, I remember thanks to google, at least one very old–in internet years–post), I’ve pushed back against criticisms of genome-wide association studies using SNP genotyping arrays. This is despite the fact that I agree it’s clear that rare variants contribute to common diseases, and that sequencing technologies are eventually going to replace genotyping arrays for most genome-wide association studies. I’ve thought a bit about why I feel the need to push back on this (I’m not involved in any studies of common diseases, for what it’s worth), and I think there are two, entirely non-scientific reasons.

1. The self-aggrandizing tone and straw man arguments. McClellan and King, in their essay on the subject, refer to the “realization” that rare variants influence common diseases as a “paradigm shift”. This would seem to imply that no one had thought about this subject before, which is obviously preposterous. Almost a decade ago, at least a couple people crunched some numbers, and found that rare variants were likely to contribute quite a bit to common diseases. The relative contributions of alleles at different frequencies depends on a number of a priori unknowable parameters, of course, so what did you expect people to do? They could either sit on their hands for a decade or two and let sequencing technologies progress, or they could hope that the value of those parameters for their disease of interest were favorable, and give it a shot. For many diseases, this paid off. For a few, it has been overwhelmingly successful. Have these same people been chomping at the bit to look at rare (or rarer) variants as technologies have progressed? Of course; anyone who presents the idea of using sequencing technologies to understand disease as novel is confused.

2. Insufficient amount of awe. Yes, ok, the genetic associations identified for many traits explain, at best, a few percent of the variance (the alternative approaches that were feasible a few years ago–ie. sitting on your hands or doing candidate gene studies–would have yielded associations that explain 0% of the variance, of course, but I suppose that’s neither here nor there). But many of those associations are really cool. A variant that influences prostate cancer risk has the opposite effect on type II diabetes, providing evidence that the negative correlation between the two diseases is partially genetic. A number of associated alleles in several diseases have different effects depending on whether they were inherited maternally or paternally. A region influencing cancer risk exerts its effect by looping over 300,000 bases away to interact with a gene’s promoter. A SNP in a gene cluster that influences body patterning during development influences variation in number of teeth at the age of one. And now you want to argue we haven’t learned anything from genome-wide association studies? Are you kidding?

In any case, nothing of the above is particularly objective–maybe there are people out there who are absolutely shocked that common SNPs aren’t everything, or who think anything which isn’t immediately medically applicable is a waste of time. But for what it’s worth (not much), I’ll point out again that genome-wide association studies have revolutionized the study of human traits; the identification of genes involved in traits has become so routine that for some it’s even now boring!

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