Recent progress in the genetics of common obesity

Abstract

The genetic contribution to interindividual variation in common obesity has been estimated at 40-70%. Yet, despite a relatively high heritability, the search for obesity susceptibility genes has been an arduous task. This paper reviews recent progress made in the obesity genetics field with an emphasis on established obesity susceptibility loci identified through candidate gene as well as genome-wide studies. For the last 15 years, candidate gene and genome-wide linkage studies have been the two main genetic epidemiological approaches to identify genetic loci for common traits, yet progress has been slow and success limited. Only recently have candidate gene studies started to succeed; by means of large-scale studies and meta-analyses at least five variants in four candidate genes have been found to be robustly associated with obesity-related traits. Genome-wide linkage studies, however, have so far not been able to pinpoint genetic loci for common obesity. The genome-wide association approach, which has become available in recent years, has dramatically changed the pace of gene discoveries for common disease, including obesity. Three waves of large-scale high-density genome-wide association studies have already discovered at least 15 previously unanticipated genetic loci incontrovertibly associated with body mass index and extreme obesity risk. Although the combined contribution of these loci to the variation in obesity risk at the population level is small and their predictive value is typically low, these recently discovered loci are set to improve fundamentally our insights into the pathophysiology of obesity.

Figure 1

Effect sizes [odds ratios (OR)] for risk of obesity reported for the established obesity-susceptibility loci discovered through three waves of large-scale high-density genome-wide association studies for body mass index (BMI) and extreme obesity risk. Effect sizes represent the increased odds of obesity for each additional risk-allele. ORs for PTER and NPC1 were inferred from the OR reported for the dominant model. Frayling et al. (2007) (); Loos et al. (2008) (); Willer et al. (2009) (); Thorleifsson et al. (2009) (○); Meyre et al. (2009) ()