Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies

Abstract

The D2 dopamine receptor mediates neuropsychiatric symptoms and is a target of pharmacotherapy. Inter-individual variation of D2 receptor density is thought to influence disease risk and pharmacological response. Numerous molecular imaging studies have tested whether common genetic variants influence D2 receptor binding potential (BP) in humans, but demonstration of robust effects has been limited by small sample sizes. We performed a systematic search of published human in vivo molecular imaging studies to estimate effect sizes of common genetic variants on striatal D2 receptor BP. We identified 21 studies examining 19 variants in 11 genes. The most commonly studied variant was a single-nucleotide polymorphism in ANKK1 (rs1800497, Glu713Lys, also called ‘Taq1A'). Fixed- and random-effects meta-analyses of this variant (5 studies, 194 subjects total) revealed that striatal BP was significantly and robustly lower among carriers of the minor allele (Lys713) relative to major allele homozygotes. The weighted standardized mean difference was −0.57 under the fixed-effect model (95% confidence interval=(−0.87, −0.27), P=0.0002). The normal relationship between rs1800497 and BP was not apparent among subjects with neuropsychiatric diseases. Significant associations with baseline striatal D2 receptor BP have been reported for four DRD2 variants (rs1079597, rs1076560, rs6277 and rs1799732) and a PER2 repeat polymorphism, but none have yet been tested in more than two independent samples. Our findings resolve apparent discrepancies in the literature and establish that rs1800497 robustly influences striatal D2 receptor availability. This genetic variant is likely to contribute to important individual differences in human striatal function, neuropsychiatric disease risk and pharmacological response.

Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity

“…Specifically, on the basis of the associations between ANKK1 variations and D2 receptor availability [34,35], as well as D2 receptor binding potential in humans [36]. Our results indicate that the FTO polymorphism investigated here may be less critical when sufficient D2 receptors are available but it may have adverse effects when dopaminergic transmission is limited.…”

“…The TaqIA restriction fragment length polymorphism (rs1800497) is located in the ankyrin repeat and protein kinase domain-containing protein (ANKK1) gene approximately 9 kb downstream of the D2 receptor gene [33]. In candidate gene studies, carriers of the risk allele (T allele) show diminished D2 receptor density [34,35], reduced D2 receptor binding potential [36] and an increased risk of substance abuse [37]. With regard to food intake, carriers of the ANKK1 risk allele have reduced responses to palatable and energy-dense food in brain regions involved in reward processing [38].…”

Effects of l-Tyrosine on working memory and inhibitory control are determined by DRD2 genotypes: A randomized controlled trial

“…This allele has also been associated with reduced extrastriatal D2 receptor availability (Hirvonen et al, 2009a) and lower striatal dopamine levels (Hirvonen et al, 2009b). However, a recent meta-analysis of human in vivo molecular imaging studies states that there were no replications "in which two or more comparable, independent, studies of striatal D2 receptors" tested for effects of this variant (Gluskin & Mickey, 2016). In the current study no other DRD2 variants have been tested in relation to TYR enhancement of cognitive function.…”

High and low doses of cocaine intake are differentially regulated by dopamine D2 receptors in the ventral tegmental area and the nucleus accumbens

“…However, D2Rs in the VTA, not the NAc, are responsible for regulating high-dose cocaine intake. Several Drd2 polymorphisms have been identified in humans and some of them are associated with the expression of D2Rs [47]. This study provides a strong rationale for future screening of vulnerable human subpopulation to addiction by genotyping Drd2 polymorphisms or mutations that lead to reduced Drd2 mRNA level or D2R function in the VTA and the NAc.…”