Sunday, November 02, 2008

Epistasis and Genome-Wide Association Studies   posted by ben g @ 11/02/2008 10:04:00 AM

Jim Manzi writes that it's plausible that epistatic interactions are central to complex mental phenotypes, and that they might therefore prevent genome-wide association studies from achieving much success. In the comments to a response post by Razib, Jason Malloy does a pretty good job of showing that traits like IQ are primarily additive and that epistasis therefore won't prevent successful GWA with good sample sizes. [UPDATE 06-25-2009: I've read more behavior genetics, and I'm not quite sure that Jason's view is correct. I think it's still an open question, actually.]

With all that in mind, some epistasis does exist, and it is worth uncovering. It will not be uncovered directly by genome-wide searches, though, because of multiple testing issues. Even a two-dimensional search overwhelms foreseeable sample sizes. However, a multi-step approach could work by breaking down the multiple dimensions into individual searches. Say that gene-A and gene-B only have an effect when they appear together. Thus, a GWA should pickup an effect from either gene-A or gene-B (whichever has a higher minor allele frequency, presumably), even if that effect is smaller than the overall effect of having both of them. Now, suppose we identify via GWA that gene-A is contributing to the phenotype. We could then do a second scan for interactions and identify gene-B.

Of course, scientists are not limited solely to association searches. They can also harness biological evidence of epistasis to help identify candidates. Because traits like IQ are primarily additive, epistasis is not the overwhelming bogeyman that it might first appear, and it should be possible to tackle in the years to come.

Hirschhorn, J. N., & Daly, M. J. (2005). Genome-wide association studies for common diseases and complex traits. Nature Reviews Genetics, 6, 95-108.