**4.4. Oligogenic obesity**

Oligogenic obesity or common obesity is the result of the set of behavioral, environmental and genetic factors that may influence individual responses to diet and physical activity [131] (**Figure 4**).

**Figure 4.** Gene–environment interactions in common obesity. Adapted with permission from Mutch and Clément [131].

The obesogenic changes of our environment in recent decades, especially the unlimited supply of cheap food with high palatability and high energy density, associated with genetic suscept‐ ibility are the causes of the current obesity epidemic [132].

The recent rapid rise in prevalence of childhood obesity suggests that, probably, environmental factors have a large impact on body weight in patients with common obesity although individual responses to these environmental factors are influenced by genetic factors called susceptibility genes [3].

Any of a group of alleles, at distinct gene loci that collectively control the inheritance of a quantitative phenotype or modify the expression of a qualitative character, are termed "polygenic" variants. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Potentially, many such polygenic variants play a role in body weight regulation. It is estimated that the total number of genes with a small effect most likely exceeds [133]. These genes are involved in a variety of biological functions such as the regulation of food intake, energy expenditure, carbohydrate and lipid metabolism and adipose tissue development [131]. Therefore, unlike monogenic obesity, many genes and chromosome regions contribute to common obesity phenotype.

Genome‐wide association studies have identified genetic risks for obesity. In less than 4 years, 52 genetic loci have been identified to be unequivocally associated with obesity‐related traits [134]. However, these loci have only small effects on obesity susceptibility and explain just a fraction of the total variance. As such, their accuracy to predict obesity is poor and not competitive with the predictive ability of traditional risk factors such as parental and childhood obesity. The first convincing GWAS discovery for any obesity‐related trait was made in 2007 for BMI when the *FTO* locus was found to be associated with obesity‐related traits and specifically with extreme and early‐onset obesity in children and adolescents [134–136]. Following the discovery of the *FTO* locus, one new locus near the *MC4R* was identified, a gene in which mutations are known to be the commonest cause of extreme childhood obesity. Also in recent years, other new BMI‐associated loci were discovered such as near *TMEM18* (*transmembrane protein 18*, OMIM \*613220, 2p25.3), near *KCTD15* (*potassium channel tetrameri‐ zation domain‐containing protein 15*, OMIM \*615240, 19q13.11), near *GNPDA2* (*glucosamine‐6‐ phosphate deaminase 2*, OMIM \*613222, 4p12), in *SH2B1* (*SH2B adaptor protein 1*, OMIM \*608937, 16q11.2), in *MTCH2* (*mitochondrial carrier homolog 2*, OMIM \*613221, 11p11.2), near *NEGR1* (*neuronal growth regulator 1*, OMIM \*613173, 1p31.1), near *FAIM2* (*FAS apoptotic inhibitory molecule 2*, OMIM \*604306, 12q13.12), near *SEC16B* (*SEC16, homolog of S. cerevisiae B*, OMIM \*612855, 1q25.2), near *ETV5* (*ETS variant gene 5*, OMIM \*601600, 3q27.2) and in *BDNF* (*brain‐ derived neurotrophic factor*, OMIM \*113505, 11p14.1). Although for many of these loci, associa‐ tion with BMI has been observed in children and in adolescents [64, 137], and in populations of non‐white origin, their replication has been less consistent than for the *FTO* and near‐*MC4R* loci for relatively small sample size of the replication studies [134].

Furthermore, longitudinal studies have been published in recent years that have followed up children over time; these studies indicated that GWAS‐discovered risk variants influence the development of obesity in part by accelerating weight gain during infancy and childhood [138– 140], but the mechanisms by which this occurs are not yet fully elucidated. One of the mech‐ anisms involved may be the different sense of appetite, but the results of the studies are controversial [141, 142].
