Which Dopamine Polymorphisms are Functional? Systematic Review and Meta-Analysis of COMT, DAT, DBH, DDC, DRD1-5, MAOA, MAOB, TH, VMAT1 and VMAT2

Abstract

BACKGROUND: Many polymorphisms in dopamine genes are reported to affect cognitive, imaging or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear. METHODS: We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in dopamine enzymes (COMT, DBH, DDC, MAOA, MAOB and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4 and DRD5), the dopamine transporter (DAT) and vesicular transporters (VMAT1 and VMAT2), defining functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product. RESULTS: We screened 22,728 papers and identified 255 eligible studies. We found robust and medium-tolarge effects for polymorphisms in four genes. For catechol-O-methyltransferase (COMT), the Val158Met polymorphism (rs4680) markedly impacted on enzyme activity, protein abundance, and protein stability. Dopamine-β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152 and DBH-STR polymorphisms. Monoamine oxidase A (MAOA) activity was associated with a 5’ variable number of tandem repeats (VNTR) polymorphism. Dopamine D2 receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing. CONCLUSIONS: Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for others, the evidence is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as ‘markers’ of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.