A few months ago, I mentioned an article in Cell arguing that many results of genome-wide association studies are false positives. This is obviously wrong, and this week, a pair of letters to the editor (including one by Kai Wang summarizing arguments he made in various comment threads here and elsewhere) take the authors to task. The response from McClellan and King is laden with non sequiturs and simple factual errors, but they conclude:
We understand that many believe that most GWAS findings are valid….Currently, GWAS results fail to explain the vast majority of genetic influence on any human illness. Further, most risk variants implicated by GWAS have no demonstrated biological, functional, or clinical relevance for disease.
I’ve bolded the last sentence there, because it’s somewhat ironic that this was published the day after an epic genome-wide association study titled “Biological, clinical and population relevance of 95 loci for blood lipids“. This paper is worth a read not just if you’re interested in lipids, but because of the massive effort put into functional characterization of the identified loci. For a few genes, the authors are able to show that altering the expression level of the gene in mice leads to the exact phenotype they’d expect, highlighting a number of potential therapeutic targets. At one gene, a companion paper describes a heroic series of experiments to identify the precise mechanism by which a non-coding SNP exerts its effect.
I allow myself to hope that these sorts of experiments will lead to a push back against the bizarre notion that associations between non-coding polymorphisms and disease are somehow suspect.