The genetics of obesity: A narrative review

Abstract

Monogenic obesity is a rare, early-onset, and severe form of obesity that has a Mendelian inheritance pattern, high penetrance, and large genetic effect. In contrast, common polygenic obesity is more prevalent and has pattern of heritability derived from many variants in several genes with low penetrance. This influences phenotype interaction with environmental factors. However, the influence of genetics on obesity is a continuous spectrum rather than the distinct classification. Genetic studies have found that leptin-melanocortin pathway is a key circuit in regulating appetite, satiety, and body weight, and most cases of monogenic obesity result from defects in this pathway. Genetic variations associated with common polygenic obesity have been found by population- based association studies, such as genome-wide association studies (GWAS). GWAS have discovered many obesity-associated loci, the majority of which harbor genes identified in monogenic obesity involving the leptin-melanocortin pathway. Genetic insights have enabled in not only understanding the molecular mechanisms and biology of obesity, but also in the development of novel therapeutic drugs for several types of monogenic obesity in the context of precision medicine. Moreover, therapeutic approaches could work in common polygenic obesity given that the genetic variations identified in the leptin-melanocortin circuit also plays a role in common polygenic obesity.

Obesity and Nutrigenetics Testing: New Insights

“…In contrast, polygenic obesity is more prevalent. It has a heritability pattern derived from many variants in several genes with low penetrance [ 56 ].…”

“…Several genes associated with polygenic obesity have been found in Genome-Wide Association Studies (GWAS). Most of these genes are involved in the leptin–melanocortin pathway, which regulates food intake [ 56 ]. Other pathways are also involved in the development of polygenic obesity ( Figure 1 ).…”