DRD2: Bridging the Genome and Ingestive Behavior

Abstract

Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) plays a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. We consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene * environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on dopamine receptor subtype 2 signaling.

A Brief Neuropsychological Battery for Measuring Cognitive Functions Associated with Obesity

“…Although this allows for straightforward interpretability of test results, it may not best fit potential effects of body weight status on all cognitive domains. For example, dopamine signaling, one of the major pathways considered to mediate effects of body composition on behavior , has been shown to act on cognitive functions, such as working memory and cognitive control, in an inverted U‐shaped fashion (i.e., there is an optimum level of dopamine for cognitive functions, and both lower and higher levels of dopamine are associated with lower performance) .…”

What Twin Studies Tell Us About Brain Responses to Food Cues

“…Individuals carrying risk alleles are at risk of weight gain related to hypo-responsivity to food cues or taste receipt within dorsal striatal regions (caudate) [85, 86], whereas in non-carriers, hyper-responsivity promotes obesity risk. While the interpretation of such findings as a deficit in experienced reward has been debated [87, 88], inherited variability in dopamine-dependent neural signaling clearly influences components of CNS appetite regulation and obesity risk directly [89, 8, 90] and via interactions with other risk genes [84, 91]. …”

DRD2/ANKK1 Taq1A but not COMT single nucleotide polymorphisms contribute to the link between temporal impulsivity and obesity in men

“…In that report, however, authors admit that some of the studies show significant interactions of DRD2/ANKK1 polymorphism and BMI and that these might be true under some circumstances, for example in morbidly obese participants. Sun and colleagues, however, argue that the negative results might be related to the fact that analysed studies reported results in very small samples 40 . According to the authors, the DRD2/ANKK1 polymorphism explains only a small portion of variance in BMI and studies would therefore require large sample sizes to find significant associations.…”

“…As a consequence of this SNP, availability of D2 receptors in the brain decreases 31–34 . This polymorphism and decreased D2 receptor density are related to addictive disorders and decreased cognitive functioning 15,35–40 . Regarding delay discounting, two studies in healthy participants showed that A1 allele carriers exhibit greater temporal impulsivity 10,41 , while another study in pathological gamblers showed no associations of temporal impulsivity and DRD2/ANKK1 Taq1A SNP 11 .…”

“…However, PET data in humans suggest that, in obese individuals, increased delay discounting rates might be related to a lower D2 receptor binding potential in the putamen 23 . The literature in the context of obesity, however, is inconsistent 40,42 and a recent meta-analysis showed that there are most likely no effects of Taq1A polymorphism on BMI 43 .…”