Thursday, March 05, 2009

Finding rare variants involved in disease   posted by p-ter @ 3/05/2009 08:01:00 PM

It has been noticed in some diseases that common variants which lead to modest increases in risk are located in or near genes that also, when mutated, cause severe monogenic forms of a the same disease (eg. obesity). This naturally leads to the hypothesis that newly identified genes containing modest risk alleles will also contain rarer alleles of strong effect.

A new study tests this hypothesis in type I diabetes: the authors take 10 genes known to be involved in diabetes etiology (note that many of these genes were discovered by genome-wide association studies of common variants) and re-sequence them in a large set of cases and controls.

What do they find? As hypothesized, a number of rare protein-altering changes in one of the genes (IFIH1, a gene involved in response to viral infection) end up being strongly associated with type I diabetes. The effect sizes aren't massive (the risk alleles have odds ratios around 2), but they certainly have stronger effects than the common variants identified (though because of their low frequencies, they explain only a minimal fraction of all the variance in diabetes risk).

This is only a proof-of-principle-- expect many similar studies, including full exome re-sequencing, in the years to come.