rs1800497 — DRD2/ANKK1 TaqIA (Glu713Lys)

The Reward Gene — Why Some Brains Need More to Feel Satisfied

In 1990, Kenneth Blum and Ernest Noble published a landmark paper in JAMA¹¹ landmark paper in JAMA
Blum K, Noble EP et al. Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA, 1990 linking a genetic marker near the dopamine D2 receptor gene to severe alcoholism. That marker, called TaqIA, became one of the most studied polymorphisms in behavioral genetics. Over three decades later, we know it affects far more than alcohol: this single nucleotide change influences how densely your brain populates its reward circuits with D2 dopamine receptors, shaping everything from how you learn from mistakes to how vulnerable you are to addictive behaviors.

What makes TaqIA unusual is a case of mistaken genomic identity. For years it was attributed to the DRD2 gene itself. In 2004, Neville and colleagues²² Neville and colleagues
Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat, 2004 discovered that the variant actually sits in exon 8 of an adjacent gene called ANKK1 (ankyrin repeat and kinase domain containing 1), which encodes a serine/threonine kinase³³ serine/threonine kinase
A type of enzyme that modifies proteins by adding phosphate groups to serine or threonine amino acids, regulating cell signaling pathways. Despite living in ANKK1's coding region, TaqIA's primary impact appears to be on D2 receptor expression in the striatum — the brain's reward hub.

The Mechanism

The A allele (historically called A1) causes a glutamic acid-to-lysine substitution at position 713 of the ANKK1 protein, within its eleventh ankyrin repeat⁴⁴ ankyrin repeat
Ankyrin repeats are structural motifs that mediate protein-protein interactions. They are found in many signaling proteins and help assemble molecular complexes. While this change doesn't destroy ANKK1's kinase activity, it may alter its substrate-binding specificity. Through mechanisms still being clarified, the A1 allele is associated with reduced D2 dopamine receptor density in the striatum⁵⁵ striatum
The striatum is a cluster of interconnected nuclei (caudate and putamen) deep in the brain that serves as the main input hub of the basal ganglia. It is central to reward processing, habit formation, and motor control.

A 2016 meta-analysis of PET imaging studies⁶⁶ 2016 meta-analysis of PET imaging studies
Smith CT et al. Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies. Transl Psychiatry, 2016 pooling five studies with 194 healthy participants confirmed that A1 carriers have significantly lower striatal D2 receptor binding (weighted standardized mean difference -0.57, 95% CI -0.87 to -0.27, p = 0.0002). This variant explains approximately 7% of the variance in striatal D2 receptor availability.

Fewer D2 receptors means the brain's reward system is less sensitive to dopamine. To achieve the same subjective sense of reward or satisfaction, A1 carriers may need more intense or more frequent stimulation — a concept Blum termed "reward deficiency syndrome"⁷⁷ Blum termed "reward deficiency syndrome"
Blum K et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs, 2000.

The Evidence

Addiction and substance use. The most replicated finding is the association with alcohol dependence. A 2013 meta-analysis of 61 studies⁸⁸ 2013 meta-analysis of 61 studies
Wang F et al. A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence. Hum Genet, 2013 covering 18,730 participants found a significant association (allelic OR 1.19, genotypic OR 1.24). The effect was consistent in European populations and remained stable after correction for publication bias. Associations with smoking have also been reported, with A1 carriers showing higher smoking rates (pooled OR 1.50 across multiple studies).

Reward processing and learning. In an influential fMRI study⁹⁹ fMRI study
Jocham G et al. Dopamine DRD2 polymorphism alters reversal learning and associated neural activity. J Neurosci, 2009, A1 carriers showed impaired reversal learning — they were worse at switching behavior after feedback changed, and had altered neural responses in the rostral cingulate zone. A 2008 Science paper by Stice and colleagues¹⁰¹⁰ 2008 Science paper by Stice and colleagues
Stice E et al. Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele. Science, 2008 demonstrated that among A1 carriers, higher BMI correlated with progressively blunted striatal activation during food consumption — suggesting a feed-forward cycle where reduced reward sensitivity drives compensatory overeating.

ADHD and attention. A meta-analysis of 11 studies¹¹¹¹ meta-analysis of 11 studies
Pan Y et al. Association between ANKK1 rs1800497 polymorphism of DRD2 gene and ADHD: a meta-analysis. Neurosci Lett, 2015 with 3,286 participants found the A1 allele associated with ADHD risk (OR 1.79, 95% CI 1.07-2.98 in the dominant model), though the effect was strongest in African populations and less consistent in European and Asian samples.

Functional confirmation. A 2023 Biological Psychiatry study¹²¹² 2023 Biological Psychiatry study
Montalban E et al. The addiction-susceptibility TaqIA/Ankk1 controls reward and metabolism through D2 receptor-expressing neurons. Biol Psychiatry, 2023 using a mouse model confirmed that ANKK1 is enriched in striatal D2R-expressing neurons, and that loss of ANKK1 function leads to alterations in learning, impulsivity, and body metabolism — providing direct causal evidence for the gene's role in reward circuitry.

Practical Implications

The actionable insight for A1 carriers centers on supporting dopamine production naturally and being aware of reward-seeking tendencies. The amino acid L-tyrosine¹³¹³ L-tyrosine
The direct biochemical precursor to dopamine. Tyrosine is converted to L-DOPA by tyrosine hydroxylase, then to dopamine by DOPA decarboxylase is the rate-limiting precursor for dopamine synthesis. Ensuring adequate tyrosine intake through protein-rich foods or supplementation may help maintain dopamine tone. Iron and vitamin D are cofactors in dopamine synthesis pathways — iron is required by tyrosine hydroxylase, and vitamin D receptors are expressed in dopamine-producing neurons.

Regular physical exercise is one of the most well-documented ways to upregulate D2 receptor expression naturally. Structured reward environments — breaking large goals into smaller milestones — can help compensate for reduced reward sensitivity. Perhaps most importantly, A1 carriers benefit from understanding their heightened vulnerability to addictive patterns, whether with substances, gambling, or compulsive eating.

Interactions

The COMT gene (rs4680, Val158Met) regulates dopamine breakdown in the prefrontal cortex. Individuals who carry both the ANKK1 A1 allele (reduced D2 receptor density) and COMT Met/Met genotype (slower dopamine clearance) may experience a complex dopamine imbalance: excess prefrontal dopamine coupled with reduced striatal reward sensitivity. Studies of disordered eating have found significant DRD2 x COMT gene-gene interactions affecting eating behavior and body weight regulation. The combined effect may amplify reward-seeking behavior beyond what either variant alone would predict.