Friday, December 01, 2006

Common disease, common variant   posted by p-ter @ 12/01/2006 05:38:00 PM

Crohn's disease is a common autoimmune disorder, and a model "complex" disease (one which involves a number of genetic and environmental factors). A couple genes contributing to the phenotype have been identified, but are insufficient to explain the population frequency of the disease.

A new study undertook genome-wide association using over 300,000 SNPs in the genome to identify other genetic risk factors, and came across one in the gene IL23R, a subunit of a receptor for a cytokine. The story here is two-fold: first, this is the first genome-wide association for Crohn's disease. Second, and more importantly, is the frequency of the putative causal variant (a nonsynonymous mutation in the gene): in the general population, the at-risk allele has a frequency of 93%. As the authors state:
Our discovery of an uncommon protective allele, or conversely, a very common predisposing allele, reflects a major theme in complex genetics; namely, that functional genetic variation exerts a continuum of susceptibility, neutral, and protective effects. Furthermore, alleles conferring protection against one disease may result in increased risk for another .
Complex phenotypes do not lend themselves well to headlines trumpeting "the gene for Crohn's disease" or "the gene for intelligence". The genes involved in these sorts of phenotypes will be involved in a number of processes, which ultimately play a role in the generation of a number of phenotypes. Selection acts on all of these phenotypes, so deciding a priori that a mutation involved in disease is necessarily deleterious in an evolutionary sense is not necessarily a fruitful approach.