A commentary published this week in the prestigious journal Cell is the latest salvo in the rare variants versus common variants “debate” (see my overall thoughts on this topic here). The commentary contains a number of false claims (ie. many SNP-disease associations found to date are false positives due to population structure) and non sequiturs (ie. the inability to find a known function for polymorphisms associated with disease means those polymorphisms have no effect on disease), which I’ll skip over in the interest of getting to the main point.
The conclusion of the authors, of course, is that the community should be doing full-genome resequencing of cases and controls to identify rare variants that cause disease. The more I see the argument presented as a bold “paradigm shift” (yes, believe it or not, the authors use this term), the more it makes me smile. It’s sort of like, back when the telescope was invented, someone writing a passionate essay saying, “Hey! You know where we should point this thing? The sky, you bloody idiots!”. The same people who have been very successful with genome-wide association studies using common SNPs have already begun to publish targeted resequencing studies (for example), and there’s no one in the field who hasn’t salivated over the prospect of dirt-cheap resequencing.
In any case, the authors of this essay have blinders on regarding the potential problems with this approach. As they say, the problem is in the biology. If the truth is that many common variants of extremely weak effect account for the majority of the variance in disease risk for many diseases, such is life, and resequencing studies simply won’t get around it. The authors cite a paper that argues this is exactly the case for schizophrenia, but of course don’t mention this conclusion, and seem oblivious to the problem it presents to their discussion. A prediction: after the first rounds of resequencing studies don’t account for all the so-called “missing heritability” of common diseases, the herd will come stampeding back to common variants (just as nonsensically as they seem to be stampeding away now).
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