The genetics of obesity: from discovery to biology

Abstract

The prevalence of obesity has tripled over the past four decades, imposing an enormous burden on people's health. Polygenic (or common) obesity and rare, severe, early-onset monogenic obesity are often polarized as distinct diseases. However, gene discovery studies for both forms of obesity show that they have shared genetic and biological underpinnings, pointing to a key role for the brain in the control of body weight. Genome-wide association studies (GWAS) with increasing sample sizes and advances in sequencing technology are the main drivers behind a recent flurry of new discoveries. However, it is the post-GWAS, cross-disciplinary collaborations, which combine new omics technologies and analytical approaches, that have started to facilitate translation of genetic loci into meaningful biology and new avenues for treatment.

Potential of Fatty Acid Amide Hydrolase (FAAH), Monoacylglycerol Lipase (MAGL), and Diacylglycerol Lipase (DAGL) Enzymes as Targets for Obesity Treatment: A Narrative Review

“…While our review considered only candidate gene association studies in humans involving FAAH or MGLL, a brief note on genome-wide association studies (GWAS) of obesity is worthwhile. Small-scale candidate gene associations studies, such as some of the studies reviewed here, have been useful to identify specific monogenic forms of obesity, which are inherited in a Mendelian pattern and are typically rare, severe, with early onset [75]. Such approaches can also be used to identify common variants associated with polygenic (common) obesity.…”

“…For example, candidate gene association approaches using larger samples were used to identify significant associations of variants in the CB1 receptor gene (CNR1) with obesity outcomes, which has been a reproducible association [76]. However, GWAS approaches using very large population samples are necessary to confirm the association of common variants contributing small effects to obesity [75]. Loos and Yeo (2021) extracted GWAS data from GWASCatalog, spanning from the first obesity GWAS in 2007 to 25 January 2021.…”

“…Loos and Yeo (2021) extracted GWAS data from GWASCatalog, spanning from the first obesity GWAS in 2007 to 25 January 2021. A review of these data found no SNPs in FAAH, MGLL, or DAGLA/DAGLB that showed genome-wide significant association (p < 5 × 10 −8 ) with obesity or related outcomes (also of note, no SNPs in CNR1 either) [75]. This suggests that variation in ECS genes is unlikely to make a major contribution to polygenic obesity, which is in line with the heterogeneity in results of candidate gene association studies (FAAH and obesity outcomes) we reviewed here.…”

Obesity and Eating Disorders in Children and Adolescents: The Bidirectional Link

“…In contrast, monogenic obesity is uncommon, accounting for 3 to 5% of obese children, presenting early weight gain often between the first and second year of life [18]. A mutation in the melanocortin 4 receptor gene (MC4 R) is the most common gene defect, which is associated with a severe, early form of obesity in children [19].…”

Causative Mechanisms of Childhood and Adolescent Obesity Leading to Adult Cardiometabolic Disease: A Literature Review

“…Hormones and peptides with blue text have an overall effect of stimulating appetite, while those with orange text have an inhibitory effect in this respect. Genetic mutations presenting with obesity in childhood include congenital leptin deficiency, the hypothalamic receptor for leptin mutations, alteration of POMC-aMSH pathway, and loss of function mutations of MC4R receptors [154,155]. Further detailed in Section 6.2.2.…”