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Review
. 2016 Mar 1;6(3):e747.
doi: 10.1038/tp.2016.22.

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

B S Gluskin  1   2 , B J Mickey  1   3
Affiliations
Review

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

B S Gluskin et al. Transl Psychiatry. .

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.

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Conflict of interest statement

During the 1-year period before publication, BJM was a paid consultant to Alkermes, on a topic unrelated to this work. BSG declares no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram of systematic literature search.
Figure 2
Figure 2
Forest plots of effect size for rs1800497 (Taq1A) and D2 receptor binding. Each genotype group comparison is represented by a gray square and horizontal error bars (mean and 95% confidence intervals). Square size is proportional to study weight. The solid vertical line represents the null hypothesis (no effect of the genetic variant). (a) In vivo imaging studies of healthy participants. Diamonds represent means and 95% confidence intervals for the fixed-effect model (filled diamond) and random-effects model (open diamond). The dashed vertical line is the fixed-effect weighted mean. (b) In vivo imaging studies of participants with disease. (c) Postmortem studies. BP, binding potential; Bmax, total number of receptors.
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