Dopamine Receptor D2
DRD2 Taq1A C>T
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 32.6% and 25.86% respectively (NIH) for T allele. The 1000 Genomes Project Database reports the T-allele (A1-allele) frequency as 19% in European, and 38 % in African populations.
The following T-allele (A1-allele) frequencies have been reported in various study populations: 9% in Yemenite Jews, 28% in children of mixed ethnicity, 29% in a white non-diabetic population, 50% in a black and white diabetic population, 45% in non-Asian obese Caucasians, 47% in Chinese, 80% in Cheyenne, 70% in Chinese middle-aged adults, 63% in a healthy Asian population. It has been suggested that the T-allele frequency is higher in diabetics and in Asian populations.
DRD2 Gene Detail
The DRD2 gene encodes for the most abundant dopamine receptor D2 (DRD2), which is responsible for dopamine-signalling in the brain. Although four major dopaminergic pathways are involved in various physiologic functions, the mesolimbocortical pathway is well-known for motivating food intake and driving hedonic urges and reward – these seem to play a role in both the perpetuation of drug abuse and food cravings.
The Taq1A polymorphism is reported to render the DRD2 less sensitive to dopamine stimulation, often motivating its carriers to engage in compensatory self-stimulatory behaviour such as the consumption of alcohol, abuse of drugs and bingeing of food. The T-allele (also referred to as the A1-allele) has been observed in association with obesity, whilst other studies concluded it unlikely that the T-allele is responsible for obesity and that it is not associated with BMI.
The T-allele is alternatively proposed as a marker, in mainly already obese people, of a high risk to develop altered eating behaviours that render them less likely to benefit from interventions to lose weight and less able to maintain weight loss after dieting.
DRD2 Taq1A C>T
DRD2 And Dopamine
The DRD2 gene, located at chromosome 11q23, has been linked to various addictive behaviours such as alcoholism, smoking, illicit drug use, gambling as well as overeating. DRD2, a G protein-coupled receptor with seven transmembrane domains, is the most abundant dopamine receptor located at postsynaptic dopaminergic neurons, centrally involved in reward-mediating and reward-deficiency pathways. These receptors are also found to play a role in dopaminergic pathways involved in movement, hormone production and dependency. The DRD2 gene, mainly expressed in the striatum, encodes two molecularly distinct isoforms, D2L and D2S, which forms by the mechanism of alternative splicing. These two isoforms are co-expressed in a ratio that favours the long isoform, D2L; both these are however said to possess distinct functions.
Although many neurotransmitters are involved in food intake, dopamine is most often directly implicated in food reward. Dopamine signalling is essential in the striatum, an area of the brain involved in reward and central satiety signalling. Chemically blocking dopamine signalling at the DRD2, such as with the treatment of neuropsychiatric conditions such as schizophrenia with the use of antipsychotic medications, may result in reduced satiety and thus weight gain as sometimes seen in these patients. Various areas in the brain are found to be more active during hunger and fasting in order to motivate for the consumption of energy-dense foods – these include the nucleus accumbens, ventrotegmental area, insula and the anterior cingulate cortex. It is generally seen that any disruption in the balance of the dopaminergic system can potentially influence energy intake and result in disordered eating.
It has been found that obese individuals have reduced levels of DRD2 and that these are inversely related to body weight. With the use of imaging studies, it has been shown that obese individuals have increased activation of the orbitofrontal cortex (OFC), the area in the brain responsible for instructing salivation and chewing when the person experiences subjective hunger or the desire to eat, when presented with pictures of calorie-dense foods. The repeated exposure to preferred energy-dense foods, especially those high in fat and sugar, is thought to potentially lead to binge-eating disorder and poor inhibitory control of food intake. It has been stated that the increased inclusion of high fructose corn syrup may reduce satiety and leave individuals less sensitive to the satisfaction experienced from natural-occurring sugars. In animal studies, rats encouraged to binge on sugar experienced a state of anxiety and opiate-like withdrawal when subsequently denied the intake of sugar. The consumption of sweet and fat foods increases dopamine concentrations in the nucleus accumbens, activating dopaminergic reward pathways in the brain which reinforces feelings of euphoria or pleasure. Perpetuating this reward pathway may lead to obesity in susceptible individuals.
The continuous overconsumption of food has been proposed to follow the same pattern as chronic addiction: continuing with addictive behaviours in the face of clear knowledge of the expected outcome. Heber et al. (2011) suggested that obese individuals may identify certain foods that promote continued consumption in the face of the known consequences of obesity, and although some individuals can recognise this as merely bad habits that can be altered, others seemingly feel powerless to control these urges. Evidence is mounting that similar genetic influences are responsible for addictive behaviours such as alcoholism and drug abuse as for food addiction that particularly involves sweet and fatty foods.
DRD2 And The Taq1A Polymorphism
The Taq1A polymorphism is found downstream of the DRD2 gene coding region – recent evidence shows that this SNP is also located within the coding region (in exon 8) of a neighbouring gene, ankyrin repeat and kinase domain containing 1 (ANKK1). Carriers of the T-allele have been shown to hold a 30-40% reduced brain D2 receptor density and weaker dopamine signalling compared with other individuals. There is considerable agreement that addiction to many drugs of abuse is characterised by decreased numbers of DRD2 in the striatum and the T-allele has indeed been associated with an increased risk for substance abuse disorders such as alcoholism, opioid dependence, cocaine-use and smoking. Reduced DRD2 density in T-allele carriers have also been associated with impaired glucose metabolism in the striatum and prefrontal cortex.
Many studies have reported on the positive correlation of reduced DRD2 in obesity, carbohydrate bingeing, substance use disorder and energy expenditure in T-allele carriers. It is suggested that persistent substance abuse in the T-allele carriers may be a form of self-stimulatory behaviour that compensates for insufficient dopamine activity. In line with this, stimulation of the D2 receptor shows potential in reducing cravings and reward-seeking behaviours.
Some studies have linked the T-allele with increased body fat and obesity, although a meta-analysis from Benton et al. (2016) did not find a significant association between the T-allele and BMI after the consideration of 33 relevant studies. A study from Yeh et al. (2016), aiming to investigate the relationship between food craving and food addiction questionnaires, body composition measurements and the DRD2 A1-allele (T-allele) in healthy Asian Americans, also reported no difference in BMI and percent body fat between T-allele carriers and non-carriers. The authors did however find significantly greater food cravings for carbohydrates and fast food in T-allele carriers, particularly when female.
In addition, the meta-analysis from Benton et al. (2016) established that there was no support for a Reward Deficiency Syndrome of food addiction – this theory suggests that the consumption of highly palatable foods stimulate the reward mechanisms of the brain so intensely that, to compensate, there is a reduction in the number of DRD2. Thus, the brain now requires a greater degree of stimulation to experience the same degree of reward and more food is consumed to avoid food cravings and withdrawal symptoms.
Although the meta-analysis from Benton et al. (2016) found no significant difference in the BMI of those with or without the T-allele at baseline, they did suggest that in those already obese, carrying the T-allele may be a risk factor for gaining more weight and for an increased difficulty to lose weight, possibly for psychological reasons. Various studies agree that the T-allele is not responsible for obesity in adults or children and it does not simply relate to body weight, but it may predispose to a personality that finds it difficult to respond to attempts to reduce weight.
Carriers of the T-allele have been found preoccupied with gaining weight in combination with a feeling of lack of control over their life, they have been described as novelty-seeking, rash and less able to learn from the costs of past behaviours. Benton et al. (2016) concluded that if the T-allele was associated with impulsivity, risk-taking and seeking reward, when combined with a decreased ability to learn from any negative consequences of such behaviour, this would result in an inability to respond appropriately to any attempt to reduce food intake. A reduced number of dopamine receptors have also been related to a decline in prefrontal cortex activity, which may indicate a reduction in self-control with regards to food intake in obese individuals. Similarly, the T-allele has been associated with increased emotional eating in Dutch adolescents
In line with this, Ariza et al. (2012) reported that not only did obese T-allele carriers show the greatest difficulty in performing tasks involved in executive functions, these participants also scored highest on the BITE scale (Bulimic Investigatory Test, Edenborough) and the disinhibition subscale of the 3FEQ (Three-Factor Eating Questionnaire). This implies greater overconsumption of foods associated with a loss of control over food intake – the authors stated that these results were expected since food reinforcement and impulsivity have been reported to be greater in obese T-allele carriers. The frequency of T allele carriers and non-carriers, however, did not differ between obese and control participants for either of the two genotypes.
An older study from Epstein et al. (2007) suggested that the presence of the T-allele interacts with obesity to increase food reinforcement and interacts with food reinforcement to increase energy intake; they concluded that energy intake was greatest in T-allele carriers with high food reinforcement. The reinforcing value of food is related to activity of the dopaminergic system as food consumption increases brain dopamine levels.
The T-allele has been proposed as a marker in people with high risk to develop pathological eating behaviour, rendering them unlikely to benefit from attempts to lose weight and less able to maintain weight loss after dieting. This weak response to lifestyle interventions aimed at the reduction of weight seem more pronounced in TT homozygotes.
Benton et al. (2016) stated that obesity is better seen as a behavioural disorder and the authors suggested the term of ‘eating addiction’, rather than ‘food addiction’ as this implies that obesity should not be addressed by concentrating on food itself, but rather the individual’s relationship with eating. The term ‘eating addiction’ stresses the behavioural component, whereas ‘food addiction’ is a passive process that simply befalls the individual and renders them unable to employ change. A more recent review from Lennerz et al. (2018) did however emphasise that high glycaemic index (GI) carbohydrates may be plausible triggers for food addiction and that nutrient signalling may play a role in addiction that is independent of hedonic taste signals. Dietary fat intake has been linked to food addiction in some studies, although it does not cause rapid metabolic shifts such as high GI carbohydrates which elicit the most pronounced metabolic response of all macronutrients with the immediate rise and fall of glucose and insulin levels; neither does it elicit the same opiate-like withdrawal symptoms after the food is removed such as with sugar bingeing.
A recent longitudinal study examining the effect of the Taq1A polymorphism on food intake and obesity parameters in children of mixed ethnicity has found that in the 7 to 8-year-old age group, T-allele carriers demonstrated higher energy intake from lipid-dense foods (LDF). As the T-allele is associated with a lower density of DRD2, the authors suggested that not only sugar, but also lipids generate a hedonic experience, producing a positive reinforcement that stimulates dopamine secretion in the brain to compensate the hypodopaminergic functioning.
Carbohydrate, Mindful Eating and Activity
Considering the research, it might be beneficial for T-allele carriers to moderate the intake of high GI carbohydrates as well as foods that are high in both fat and carbohydrates. Also, promote the principles of mindful eating so to manage energy intake and avoid potential triggers of overeating.
Research is suggesting that exercise and regular physical activity may be able to engage some of the same reward pathways, thus help in maintaining body weight after weight loss, by activating the same neuronal pathways involved in the instigation of overeating.
Evaluation of association of DRD2 TaqIA and -141C InsDel polymorphisms with food intake and anthropometric data in children at the first stages of development.
Feistauer et al, 2018.