Obesity is a complex, heritable trait influenced by the interplay of genetics, epigenetics, metagenomics and environment. With increasing access to highly accurate diagnostic tools for genetic research, numerous genes have been identified that influence the phenotype, especially in severe early onset obesity. Rarely, obesity runs in families in a clear pattern of inheritance caused by changes in a single gene. The most commonly implicated gene is MC4R, which encodes the melanocortin 4 receptor.
Changes in MC4R that decrease its function are found in a small fraction (. Rarely, a clear pattern of inherited obesity within 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. Most obesity appears to be multifactorial, i.e. the result of complex interactions between many genes and environmental factors.
However, major hurdles remain in the transition from conventional to precision medicine for monogenic obesity, which would require the adoption of systematic EMA for individuals suspected of carrying deleterious mutations and, eventually, even standardised screening at birth. A better explanation of obesity in terms of genes and environmental factors could help to encourage people trying to achieve and maintain a healthy weight. Broad acceptance of the biological basis of obesity would not only be fair, but would allow us to focus collectively on health. Obesity is the result of an energy imbalance that occurs when a person consumes more calories than their body burns.
Polygenic (or common) obesity and rare, severe, early-onset monogenic obesity are often polarised as distinct diseases. Ultimately, genome-wide candidate gene and linkage studies, limited by small sample sizes, poor coverage of genetic variation in the genome and lack of replication, have had only a marginal impact on the progression of gene discovery for common obesity outcomes. Gene expression at key obesity-associated loci is enriched in the insula and substantia nigra brain regions involved in addiction and reward. For example, the FTO locus, which was identified more than a decade ago and harbours six genes, is the most widely studied GWAS-identified obesity locus (Fig.
A severe, early-onset form of obesity caused by a single gene mutation, with little or no environmental influence. The subcellular localisation of MC4R with ADCY3 in neuronal primary cilia underlies a common pathway of genetic predisposition to obesity. Severe early-onset obesity, adrenal insufficiency and red-headed pigmentation caused by POMC mutations in humans. Like CADM1 and CADM2, NEGR1 is a cell adhesion molecule of the immunoglobulin superfamily that is expressed in several brain regions and has been shown to play a role in brain connectivity69,142, a process thought to be important in obesity143. Despite sample sizes of over 200,000 individuals, these genome-environment interaction (GíE) analyses remain challenging and so far only 12 loci have been identified whose effects on obesity are attenuated or exacerbated by non-genetic factors.
