The genetic determinants of common obesity-susceptibility

Abstract

Despite a relatively high heritability, the search for obesity-susceptibility genes has been challenging. While candidate gene studies and genome-wide linkage studies identified only a handful of genetic variants convincingly associated with obesity-related traits, the genome-wide association approach has truly revolutionised gene discovery for many common diseases and traits, including obesity. Over the past decade, large-scale genome-wide association studies for a range of adiposity traits, including BMI, WHR, extreme obesity, and body fat percentage, have identified at least 250 obesity-susceptibility loci, most of which had not previously been linked to body weight regulation. Although the combined contribution of these genetic loci to variation in obesity risk is small and their predictive value is low, the identified loci have shed new light on the complex physiology that governs the regulation of energy balance and fat distribution. Pathway and tissue enrichment analyses applied to associated loci have provided strong support for a role of the central neuronal system in overall obesity and of peripheral physiology in body fat distribution. The identification of new obesity genes could eventually lead to the discovery of drug targets for more effective preventive and therapeutic interventions. While the rapid progress in gene discovery has raised hopes towards the development of genetic risk profiles to guide individual weight management, the current evidence suggests that the available genetic data is not sufficient for such personalized implementations.