Obesity genes and gene-environment-behavior interactions: recommendations for a way forward.

Obesity is a classical complex trait, influenced by both genetic and lifestyle factors. The number of obesity gene variants is currently unknown but, based on sound evolutionary principles, likely to be many, each with a modest effect on the phenotype. Recent advances in our knowledge of variation in the human genome and high throughput genotyping technologies have made possible genome-wide association (GWA) analysis and the identification of bona fide susceptibility genes for many complex diseases and phenotypes, including obesity and its comorbid conditions. GWA analysis in even larger numbers of individuals through collaborative efforts of many investigators will likely identify those polygenes of moderate and modest effect size that manifest in our typical environment. Once the subset of real-world-relevant obesity susceptibility variants is identified, follow-up studies, including detailed molecular analysis of the loci, stratified analyses, prospective and interventional studies in humans, and mechanistic studies in cells and animals will allow us to define the genetic architecture of the locus and dissect how these genes interact with specific environmental and other factors. The molecular and analytical tools to accomplish these goals are now in hand, but cooperation among investigators will be necessary to amass the requisite numbers of phenotyped and genotyped individuals. Identification of susceptibility genes for obesity and determining how they interact with each other and the environment will lead to new insights into the molecular, cellular, and physiological basis of energy homeostasis, and novel strategies for prevention and treatment.