Molecular genetic aspects of weight regulation.

BACKGROUND: Family and twin studies have empirically revealed a 40% to 70% heritability of body-mass index, yet only a few hereditary factors have been identified to date that increase the risk of being overweight.
METHODS: We present the current state of molecular genetic research on obesity with a selective review of the literature.
RESULTS: A number of monogenic recessive mutations causing obesity have been identified, but these are rare. Various dominant mutations of the melanocortin-4 receptor gene are found in about 1% to 4% of all markedly obese persons. Current molecular genetic research focuses on the identification of common DNA variants affecting body weight; the genetic material of hundreds of thousands of people from around the world has now been investigated in genome-wide association studies. More than 30 variants conferring an increased risk have been identified, most of which are single nucleotide polymorphisms (SNPs) of no immediately clear functional significance. On average, these variants raise body weight by 500 g (range, 180 to 1400 g). Aside from SNPs, variations in the number of copies of specific DNA sequences have also been linked to obesity, as well as to subnormal weight. All the hereditary factors that have been identified to date account for about 5% of the variability of BMI. Extrapolation yields figures ranging from 10% to 15%.
CONCLUSIONS: The amount of genetic variability seen to date at the DNA level accounts only for a small fraction of the inter-individual variability of BMI. Obesity is thought to be a largely hereditary condition; the fact that its genetic basis has not yet been demonstrated may be due to various genetic or experimental factors.