Genetics may be the direct cause of obesity in specific disorders such as Bardet-Biedl syndrome and Prader-Willi syndrome. However, genes do not always predict future health. Both genes and behaviour may be necessary for a person to become overweight. Rarely, a clear pattern of inherited obesity in a family is caused by a specific variant of a single gene (monogenic obesity).
However, most obesity is probably the result of complex interactions between multiple genes and environmental factors that remain poorly understood (multifactorial obesity). Work on gene-environment interactions related to obesity is still in its infancy. So far, evidence suggests that genetic predisposition is not destiny: many people carrying so-called "obesity genes" do not become overweight. Rather, it appears that eating a healthy diet and getting enough exercise may offset some of the gene-related risk of obesity.
Obesity is a complex inherited trait influenced by the interaction of genetics, epigenetics, metagenomics and environment. With increasing access to highly accurate diagnostic tools for genetic investigations, numerous genes have been identified that influence phenotype, especially in severe early-onset obesity. This review summarises the current knowledge on the known genetic causes of obesity and the available therapeutic options. In addition, the role and potential mechanism of epigenetic changes that may be involved in mediating environmental influences are discussed and may provide future opportunities for intervention.
There is no single factor or behaviour that causes obesity. Obesity is caused by many things, such as a person's habits, lifestyle and environment. Genes and some medical problems also increase a person's chances of being obese. Since the first GWAS for BMI68,117 , these analyses have pointed to the CNS as a key player in the regulation of body weight, in line with findings from human and animal models of extreme obesity.
Once the leptin and leptin receptor genes were identified, they became candidate genes for human obesity, and in 1997 the first humans with congenital leptin deficiency were identified21. Gene discovery is often dichotomised by allele frequency and disease prevalence, i.e. mutations are sought for monogenic forms of obesity and common variants for polygenic obesity (Fig. There may be a hitherto unidentified shared basis for obesity and neurodevelopmental defect(s).
In these syndromes, obesity is often accompanied by mental retardation, reproductive abnormalities or other problems. Genetic variants in LEP, LEPR and MC4R explain 30 percent of severe obesity in children in an inbred population. These data support the premise that multiple rare alleles contribute to variation in susceptibility to obesity in the general population. Epidemiological studies have provided evidence for the presence of obesity and metabolic changes in the offspring of EDC-exposed mothers, probably mediated by epigenetic changes.
Thoughtful consideration of genetic causes and understanding the growing evidence of epigenetic changes influencing the growing obesity epidemic provide valuable tools for the clinician in the management of obesity. However, variation in the way people respond to the same environment suggests that genes play a role in the development of obesity. Congenital leptin deficiency follows a recessive mode of inheritance, and was first identified in two extremely obese first-degree cousins from a Pakistani family, caused by a frameshift mutation (c.
