Sunday, May 04, 2008

Weight and genetics   posted by p-ter @ 5/04/2008 08:20:00 PM

Two studies report this week on the association of variation near MC4R with body mass. This is the second convincingly replicated locus to be implicated in natural variation in weight, the first being FTO. There are a couple reasons I find this association interesting.

1. Coding mutations in MC4R are known to cause severe obesity. It's to be expected that less severe mutations (the region of the genome implicated in these studies is likely regulatory) could lead to more subtle effects on body weight, but it didn't have to be that way. And this forms part of a pattern that genes that cause Mendelian forms of a disease are also associated with more common forms as well. Why is this interesting? It suggests that the candidate gene approach to finding allele associated with disease wasn't as flawed as people thought--it's just that they were all severely underpowered (the number of individuals in these studies, for example, tops 60,000).

2. One of the studies performed their association study in individuals of Indian descent. This is one of the first GWA studies to focus on a non-European population--a development that will hopefully continue. Insofar as allele frequencies vary among populations, studies of the same phenotype in different populations may get quite different results (note that studies of skin pigmentation in Europeans don't identify SLC24A5, but studies in South Asians do--the reason is that the relevant variant in the gene is fixed in Europe but at moderate frequency in India). Population genetics has always had a role in the rational choice of study population for association studies, but as all the low-hanging fruit gets taken, this role will perhaps become more pronounced.