Genetics of human obesity.

Most human obesity is due to multiple susceptibility genes interacting in complex ways with each other and with environmental factors. It is estimated that 40–70% of the within-population variation in obesity is due to genetic variation, although genes identified to date explain less than 10% of that heritability. Monogenic (single-gene) obesity, whether uncomplicated or associated with genetic syndromes, is rare. Nevertheless, much of what is known about the genetics of human obesity comes from studies of monogenic obesity in both humans and mice. Nine genes known to cause monogenic obesity in humans are components of the hypothalamic leptin–melanocortin pathway that functions to control whole body energy balance. Certain mutations in the genes of the leptin–melanocortin pathway, most commonly the melanocortin 4 receptor, are also found to contribute to common, multigenic obesity. The function of the recently discovered fat mass and obesity-associated gene is unknown, although it is significantly associated with multigenic obesity in many populations. Syndromic obesities can be identified by a wide spectrum of characteristic phenotypes and by cytogenetics assays. Monogenic, nonsyndromic obesities are more difficult to diagnose. There are no clinical assays for these mutations, and the only diagnostic tools are for endocrine abnormalities. Patients with monogenic obesity will likely be more difficult to treat than those with multigenic obesity. Gastric bypass surgery may be less effective in patients with a high obesity allele burden. Drugs targeted at components of the leptin–melanocortin pathway may one day offer more effective treatments to all obese patients.