Obesity genetics and epigenetics: dissecting causality.

Abstract

Genome-wide association studies (GWAS) have successfully revealed multiple obesity-associated genetic loci1. A strong reproducible signal comes from a cluster of the variants that lie in the 47-kb region of the first and second intron of fat mass and obesity associated ( FTO ) gene2,3. Each copy of the risk allele of FTO variants is associated with a 1.2-fold increased risk of obesity and an increase in body weight of ≈2.5 pounds. Until recently, mechanistic studies designed to explain the association of non-coding FTO variants did not yield any direct evidence of how these single-nucleotide changes may affect FTO expression or function of the protein. In a study by Smemo et al,4 the authors provided proof of principle to the model that the linear distance between 2 regions on a chromosome is not an impediment when it comes to decoding functionality of the GWAS-associated variants. In a multidisciplinary effort, the authors4 convincingly demonstrate that the noncoding FTO variants act as enhancer elements and interact with the promoter sequence required for expression of a distant Iroquois-class homeodomain protein 3 ( IRX3 ) gene. The authors profiled the genomic interactions with promoters of genes located within a 1-Mb region around the obesity-associated variants. They used circular chromosome conformation-capture followed by …