Monday, October 06, 2008

Following up association studies   posted by p-ter @ 10/06/2008 07:55:00 PM

Many recent posts on this site have been dedicated to genome-wide association studies, in which variants across the genome are tested for their association with a phenotype. These studies, if successful, identify a relatively small candidate region that presumably contains some sort of polymorphism that plays a role in the phenotype. Identifying that causal polymorphism is far from trivial.

A recent study on cleft lip provides a glimpse into how these sorts of follow-up might proceed. The authors had earlier shown (through a candidate gene study) that SNPs in IRF6 (a transcription factor) were associated with cleft lip. In particular, a non-synonymous SNP in the gene was repeatedly and reliably associated with the phenotype. In this follow-up study, however, the authors find another, non-coding SNP that shows the strongest association with the phenotype.

The authors are then able to show that this SNP falls in a binding site for another transcription factor, and that the region is an enhancer element that drives expression of IRF6 in the developing face. They don't show that the SNP changes expression patterns, but it's still a pretty impressive piece of work, and exemplifies the extensive experimental work that will be needed to ultimately refine the glut of genome-wide association signals being published.