Genetics of obesity
Like many other medical conditions, obesity is the result of an interplay between environmental and genetic factors. Studies have identified variants in several genes that may contribute to weight gain and body fat distribution, although only in a few cases are genes the primary cause of obesity. Recent research indicates that environmental influences can lead to epigenetic modifications affecting gene expression related to obesity. These changes can alter metabolic processes and appetite regulation, contributing to obesity development.
Polymorphisms in various genes controlling appetite and metabolism predispose to obesity under certain dietary conditions. The percentage of obesity that can be attributed to genetics varies widely, depending on the population examined, from 6% to 85%, with the typical estimate at 50%. Twin studies have consistently shown that genetics account for 40% to 70% of the variation in body mass index across individuals. It is likely that in each person a number of genes contribute to the likelihood of developing obesity in small part, with each gene increasing or decreasing the odds marginally, and together determining how an individual responds to the environmental factors. As of 2006, more than 41 sites on the human genome have been linked to the development of obesity when a favorable environment is present. Some of these obesogenic or genes may influence the obese individual's response to weight loss or weight management.
Epigenetic influences and environmental interactions
Epigenetics plays a critical role in obesity susceptibility. Environmental exposures, such as poor maternal nutrition and exposure to endocrine-disrupting chemicals, can induce epigenetic modifications that alter gene expression without changing the DNA sequence. Research on epigenetic transgenerational inheritance suggests that environmental insults can reprogram the epigenome of germline cells, leading to obesity susceptibility in future generations.Gene-environment interactions further complicate obesity risk. Certain genetic variants modify an individual's response to dietary intake, physical activity, and other lifestyle factors. For example, some individuals with specific FTO variants may have an increased appetite and lower satiety, predisposing them to higher caloric intake and weight gain. Conversely, adherence to a healthy diet can significantly reduce the genetic effects on body mass index, emphasizing the importance of lifestyle modifications even in genetically predisposed individuals.
Specific genetic mechanisms
Although genetic deficiencies are currently considered rare, variations in these genes may predispose to common obesity. Many candidate genes are highly expressed in the central nervous system. The development of genetic tests, such as MyPhenome, enables the classification of obesity into specific subtypes based on genetic and phenotypic data. This stratification allows for personalized treatment approaches, improving the effectiveness of obesity interventions. Research has identified genes associated with obesity in both humans and animals. For example, the DENND1B gene has been linked to obesity in Labrador retrievers and humans, highlighting shared genetic factors influencing weight gain across species.Several additional loci have been identified. Also, several quantitative trait loci for BMI have been identified.
Confirmed and hypothesized associations include:
| Condition | OMIM | Locus | Notes |
| leptin deficiency | 7q31.3 | ||
| leptin receptor deficiency | 1p31 | ||
| Ghrelin | 3p25.3 | ||
| Ghrelin receptor | 3q26.31 | ||
| prohormone convertase-1 deficiency | 5q15-q21 | ||
| proopiomelanocortin deficiency | 2p23.3 | ||
| melanocortin-4 receptor polymorphism | 18q22 | ||
| 7q32.3 | near D7S1804 | ||
| 13q14 | near D13S257 | ||
| 6q23-q25 | near D6S1009, GATA184A08, D6S2436, and D6S305 | ||
| 11q24 | near D11S1998, D11S4464, and D11S912 | ||
| 16p13 | near ATA41E04 | ||
| 20pter-p11.2 | near D20S482 | ||
| INSIG2 | 2q14.1 | ||
| FTO | 16q12.2 | Adults who were homozygous for a particular FTO allele weighed about 3 kilograms more and had a 1.6-fold greater rate of obesity than those who had not inherited this trait. This association disappeared, though, when those with FTO polymorphisms participated in moderately intensive physical activity equivalent to three to four hours of brisk walking. | |
| TMEM18 | 2p25.3 | ||
| GNPDA2 | 4p13 | ||
| NEGR1 | 1p31.1 | ||
| BDNF | 11p13 | ||
| KCTD15 | 19q13.12 | KCTD15 plays a role in transcriptional repression of AP-2α, which in turn, inhibits the activity of C/EBPα, an early inducer of adipogenesis. | |
| ? | Although it does not play a role in the formation of fat itself, it does determine the location on the body where this fat is stored. | ||
| SH2B1 | 16p11.2 | ||
| MTCH2 | 11p11.2 | ||
| PCSK1 | 5q15-q21 | ||
| NPC1 | 18q11-q12 | ||
| LYPLAL1 | 1q41 | Disputed metabolic function of being either a lipase or a short-chain carboxylesterase. | |
| CB1 | 6q15 | ||
| NPY5R | 4q32.2 |
Some studies have focused upon inheritance patterns without focusing upon specific genes. One study found that 80% of the offspring of two obese parents were obese. In contrast, less than 10% of offspring of two parents who were of normal weight were obese.
The thrifty gene hypothesis postulates that due to dietary scarcity during human evolution people are prone to obesity. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would more likely survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies. This is the presumed reason that Pima Native Americans, who evolved in a desert ecosystem, developed some of the highest rates of obesity when exposed to a Western lifestyle. Emerging research suggests that genetic factors may contribute to the common phenomenon of weight regain after weight loss, known as yo-yo dieting. These genetic influences can affect metabolic rate and appetite regulation, making sustained weight loss challenging for some individuals.
Numerous studies of laboratory rodents provide strong evidence that genetics play an important role in obesity.
The risk of obesity is determined by not only specific genotypes but also gene-gene interactions. However, there are still challenges associated with detecting gene-gene interactions for obesity.