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Functional Effects of Dopamine Transporter Gene Genotypes on in Vivo Dopamine Transporter Functioning: a Meta-Analysis

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Functional Effects of Dopamine Transporter Gene Genotypes on in Vivo Dopamine Transporter Functioning: a Meta-Analysis Molecular Psychiatry (2014) 19, 880–889 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis SV Faraone1, TJ Spencer2, BK Madras3,4, Y Zhang-James1 and J Biederman2 Much psychiatric genetic research has focused on a 40-base pair variable number of tandem repeats (VNTR) polymorphism located in the 30-untranslated region (30UTR) of the dopamine active transporter (DAT) gene (SLC6A3). This variant produces two common alleles with 9- and 10-repeats (9R and 10R). Studies associating this variant with in vivo DAT activity in humans have had mixed results. We searched for studies using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) to evaluate this association. Random effects meta-analyses assessed the association of the 30UTR variant with DAT activity. We also evaluated heterogeneity among studies and evidence for publication bias. We found twelve studies comprising 511 subjects, 125 from PET studies and 386 from SPECT studies. The PET studies provided highly significant evidence that the 9R allele was associated with increased DAT activity in human adults. The SPECT studies were highly heterogeneous. As a group, they suggested no association between the 30UTR polymorphism and DAT activity. When the analysis was limited to the most commonly used ligand, [123I]b-CIT, stratification by affection status dramatically reduced heterogeneity and revealed a significant association of the 9R allele with increased DAT activity for healthy subjects. In humans, the 9R allele of the 30UTR polymorphism of SLC6A3 regulates dopamine activity in the striatal brain regions independent of the presence of neuropsychiatric illness. Differences in study methodology account for the heterogeneous results across individual studies. Molecular Psychiatry (2014) 19, 880–889; doi:10.1038/mp.2013.126; published online 24 September 2013 Keywords: ADHD; dopamine transporter; genetics; meta-analysis; PET; SPECT INTRODUCTION model of ADHD.3 Based on a meta-analysis of nine in vivo 15 The dopamine active transporter (DAT) is a key regulator of the SPECT and PET studies, Fusar-Poli et al. concluded that DAT dopamine system and the gene that encodes it (SLC6A3) has been activity was 14% higher in ADHD patients compared with controls the focus of much research in biological psychiatry, having been and that, among ADHD patients, DAT activity was higher among implicated in several disorders including attention deficit hyper- patients with a history of medication (although this latter activity disorder (ADHD),1–3 pediatric bipolar disorder,4 Tourette conclusion has been questioned due to incorrect coding of 16 syndrome5 and alcoholism,6 but not schizophrenia.7 Much medication status. ) research in this area has focused on the DAT gene (SLC6A3), Functional in vitro studies have shown mixed results as to especially a 40-base pair variable number of tandem repeats whether it is the 9R or 10R allele that increases DAT gene 17–21 (VNTR) polymorphism located in the 30-untranslated region expression. These results varied in the reporter gene designs (30UTR) of the gene, which has a regulatory role during and cell types used. A few studies measured in vivo striatal DAT gene transcription. This variant produces two common alleles with expression using postmortem brains, and the results were also 22–25 9- and 10-repeats (9R and 10R). In humans, meta-analyses suggest inconsistent. MRI and magnetic resonance spectroscopy studies 26–28 the 10R allele of this polymorphism is associated with ADHD in have also produced heterogeneous results. Areviewof youth8 whereas the 9R allele is associated with ADHD in adults.9 neuropsychological studies found little evidence supporting the 29 Meta-analysis also associates the 9R allele with alcoholism,6 a idea that the SLC6A3 30UTR is associated with deficits in cognition, 27 common comorbidity of ADHD in adults. with the possible exception of functions mediated by the striatum. The DAT was initially implicated in ADHD by the stimulant PET and SPECT neuroimaging studies have examined the drugs, which are efficacious for the disorder and block the DAT, association of the 30UTR polymorphism with in vivo striatal DAT thereby increasing the concentration of dopamine in the synaptic binding in humans. Such studies are particularly compelling cleft. These effects are most pronounced in the nucleus accum- because they directly measure the protein produced by the gene bens and dorsal striatum due to the high density of DATs in these rather than measuring mRNA level, or downstream effects of brain regions.10,11 Positron emission tomography (PET) studies in activation or cognition. DAT binding may be an intermediate humans show that both methylphenidate12 and amphetamine13 phenotype that mediates the effects of DAT gene variants on increase extracellular dopamine levels in the striatum. Single- dopamine-regulated brain functions and, ultimately, a wide array photon emission tomography (SPECT) and PET studies also show of behavior; including information processing, inhibition, emotion, that methylphenidate treatment blocks the DAT.14 Consistent with movement, salience and reward. Advances in molecular imaging this, methylphenidate normalizes elevated DAT densities in a rat and the development of highly specific DAT binding ligands allow 1Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA; 2Pediatric Psychopharmacology Unit, Psychiatry Service, Massachusetts General Hospital, Department of Psychiatry, Harvard Medical School, Boston, MA, USA; 3Division of Neuroscience, New England Primate Research Center, Southborough, MA, USA and 4Harvard Medical School, Boston, MA, USA. Correspondence: Dr SV Faraone, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. E-mail: [email protected] Received 20 February 2013; revised 15 August 2013; accepted 16 August 2013; published online 24 September 2013 Meta-analysis of dopamine transporter gene associations SV Faraone et al 881 Records identified through Additional records identified database searching through other sources (n = 105) (n = 1) Identification Records after duplicates removed (n =106) Screening Records screened Records excluded (n =106) (n =88) Full-text articles excluded, Full-text articles assessed with reasons for eligibility (n = 6) (n =18) Wrong type of study, i.e., no human dopamine Eligibility transporter genotype or imaging data Studies included in qualitative synthesis (n = 12) Studies included in Included quantitative synthesis (meta-analysis) (n = 12) Figure 1. PRISMA flow diagram. Note: PRISMA ¼ Preferred reporting items for systematic reviews and meta-analyses (http://www.prisma- statement.org/). for the imaging of the DAT in humans facilitating the direct in vivo SPECT) and, for SPECT studies, type of ligand. As we show in this examination of the product of the DAT gene and its polymorph- manuscript, attending to these key issues provides a better isms in humans. Thus, studies of the SLC6A3 30UTR polymorphism understanding of the association between the SLC6A3 30UTR and DAT binding provide evidence as to whether this polymorph- polymorphism with in vivo striatal DAT binding in humans. ism regulates DAT functioning in living humans. Results from such in vivo studies could advance our under- standing of the genetic control of dopamine as an important neuromodulator of brain function. However, they have produced METHODS mixed results. Only two PET studies addressed this issue. These A PubMed literature search identified studies that met the following criteria: (1) use of SPECT or PET to assess DAT availability in the brains of studies of striatal structures reported that the 9R allele was 0 30,31 human subjects; (2) genotyping of the DAT gene (SLC6A3)3UTR VNTR. (3) associated with increased DAT activity. In contrast, ten SPECT reporting of means and standard deviations of DAT availability stratified by studies produced conflicting results. A meta-analysis of eight of genotype; (4) reporting of the numbers of subjects in each genotype these SPECT studies concluded that these studies did not provide group. We used the following search algorithm in PubMed: ‘dopamine support for the putative association between the SLC6A3 30UTR transporter’ [TIAB] OR DAT1[TIAB] OR SLC6A3[TIAB] AND (imaging [TIAB] OR polymorphism and DAT activity in the brain.32 single-photon [TIAB] OR SPECT [TIAB] OR PET [TIAB] OR ‘positron emission In vivo imaging of DAT is particularly relevant for ADHD given tomography’[TIAB]) AND (genetic [TIAB] OR genotype [TIAB] OR genotypes that DAT is the target of stimulant medications and, subsequently, [TIAB] OR allele [TIAB] OR alleles [TIAB] OR polymorphism [TIAB]). If the a target protein for studies of pathophysiology. Clarifying the reference sections of any of these articles suggested additional articles, nature of the association of SLC6A3 variants would provide a key these were also examined. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram in Figure 1 describes the step towards identifying part of ADHD’s pathophysiology. number of articles identified and their disposition. If the required data Depending upon the strength of the relationship, it could point were not available in relevant articles, we contacted authors for that data toward a means
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