Genes Connected to Obesity
Based on current evidence, the 15 genes known to be connected to obesity include FTO, MC4R, POMC, PCSK1, LEP, LEPR, SIM1, BDNF, NTRK2, TCF7L2, CDKAL1, HHEX/IDE/KIF11, GRB14, ST6GAL1, and HMG20A. 1, 2
Monogenic vs. Polygenic Obesity
Obesity has a strong genetic component that may contribute up to 70% of disease risk 3. The genetic basis of obesity can be classified into two main categories:
Monogenic Obesity
- Caused by mutations in single genes that play critical roles in appetite regulation and energy homeostasis 2
- Key genes involved in monogenic obesity include:
- LEP (leptin) - Controls satiety signals 2
- LEPR (leptin receptor) - Mediates leptin's effects on appetite 2
- POMC (proopiomelanocortin) - Precursor for several hormones involved in appetite regulation 1
- PCSK1 (prohormone convertase 1) - Processes prohormones into active forms 2
- MC4R (melanocortin 4 receptor) - Central regulator of food intake and energy expenditure 1
- SIM1 (single-minded homolog 1) - Transcription factor involved in hypothalamic development 2
- BDNF (brain-derived neurotrophic factor) - Regulates energy balance 2
- NTRK2 (neurotrophic tyrosine kinase receptor type 2) - Receptor for BDNF 2
Polygenic Obesity
- Most common form of obesity, involving multiple genes with small individual effects 3
- Key genes associated with polygenic obesity include:
- FTO (fat mass and obesity-associated protein) - Has the largest known genetic effect on obesity risk 1
- TCF7L2 - Associated with both obesity and type 2 diabetes 1
- CDKAL1 - Important locus for obesity and type 2 diabetes 1
- HHEX/IDE/KIF11 - Associated with metabolic disorders 1
- GRB14, ST6GAL1, HMG20A, VPS26A, and AP3S2 - Identified in genome-wide association studies as obesity-related loci 1
Mechanisms of Genetic Influence on Obesity
Central Melanocortin System
- A key pathway in energy balance regulation where signals converge on the arcuate nucleus to regulate food intake and satiety 1
- Involves several genes including FTO, MC4R, and POMC 1
- These genes are tied to neuronal controls of appetite and eating behaviors 1
Genetic Variants and Environmental Interactions
- The FTO gene has the strongest association with obesity in both adults and adolescents 4
- Homozygous individuals for the BMI-increasing allele at rs9939609 in FTO weigh approximately 3 kg more than non-carriers and have a 1.67-fold higher risk of obesity 1
- Significant interactions have been observed between dietary components and FTO in relation to obesity, including Mediterranean diet patterns, fat and carbohydrate intake, alcohol consumption, and salt intake 1
Ethnic Variations in Genetic Risk
- Genetic risk factors for obesity may vary across ethnic groups 1
- Studies in South Asian populations have identified both shared and unique genetic associations with obesity compared to European populations 1
- Despite these variations, the underlying biological pathways appear similar across ethnic groups 1
Clinical Implications
Genetic Testing Considerations
- Genetic testing for obesity is more reliable for monogenic rather than polygenic traits 1
- For polygenic obesity, current direct-to-consumer genetic testing has limited clinical utility due to:
Future Directions
- Next-generation sequencing (NGS) is emerging as a useful tool to identify candidate genes for obesity in clinical settings 2
- Better understanding of gene-environment interactions and epigenetic mechanisms may lead to more effective prevention and intervention strategies 3, 5
- Research focusing on adipose tissue function may reveal additional genetic factors, as many obesity-related genes control adipose tissue function 6
Understanding the genetic basis of obesity is crucial for developing personalized approaches to prevention and treatment, but current knowledge suggests that environmental factors remain critically important in the expression of genetic predisposition to obesity 3, 5.