David Goldstein and collegues report today the results of a genome-wide association study for a particular side effect (treatment-induced anemia) of treatment for hepatitis C. It turns out that variants in a single gene–ITPA–are overwhelmingly associated with the development of this side effect. This is a nice, probably clinically-important result, and there’s likely some interesting biology here as well.
One twist is that the authors identify two presumably causal variants in the gene–one a nonsynonymous SNP, and the other a SNP falling in a splice site. The authors make the following point:
Two related features of these observations are worth emphasizing. First, the ITPA variants constitute a clear example of a synthetic association in which the effects of rarer functional variants are observed as an association for a more common variant present on a whole-genome genotyping chip: indeed, the minor-allele frequency is higher for the top-associated SNP rs6051702 (19.4%) than for the causal variants rs1127354 (7.6%) and rs7270101 (12.3%) in European-Americans
Some readers will recall the paper recently published by this group on “synthetic associations“, where they posited a model for common diseases in which multiple rare (< 5% minor allele frequency) SNPs in a gene can lead to identification of as association with a common allele. Now, it appears, any gene with more than one functional variant, rare or not, fits their model!
That aside, I can see their point–the patterns of linkage disequilibrium around a locus with two causal variants leads in this case to a strong association signal at a SNP that happens to be correlated with both of them. But this isn’t a new phenomenon worthy of a special name; for example, multiple correlated SNPs in the MHC influence risk for celiac disease, and most people are happy to call it that–multiple causal variants at a locus. It seems a bit like the authors are trying to shoehorn the data to fit their theories a bit awkwardly.