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Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis

Molecular Psychiatry volume 19, pages 880–889 (2014)Cite this article

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Abstract

Much psychiatric genetic research has focused on a 40-base pair variable number of tandem repeats (VNTR) polymorphism located in the 3′-untranslated region (3′UTR) 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 3′UTR 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 3′UTR polymorphism and DAT activity. When the analysis was limited to the most commonly used ligand, [123I]β-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 3′UTR 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.

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Authors and Affiliations

  1. Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    S V Faraone & Y Zhang-James

  2. Department of Psychiatry, Pediatric Psychopharmacology Unit, Psychiatry Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    T J Spencer & J Biederman

  3. Division of Neuroscience, New England Primate Research Center, Southborough, MA, USA

    B K Madras

  4. Harvard Medical School, Boston, MA, USA

    B K Madras

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  1. S V Faraone
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Correspondence to S V Faraone.

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In the past year, Dr Faraone received consulting income and/or research support from Akili Interactive Labs, VAYA Pharma and SynapDx and research support from the National Institutes of Health (NIH). His institution is seeking a patent for the use of sodium–hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. Dr Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health and Oxford University Press: Schizophrenia: The Facts. In the last two years, Dr Thomas Spencer has been an Advisor or on an Advisory Board of the following sources: Alcobra, Ironshore, the Department of Defense and the National Institute of Mental Health. In the last two years, Dr Thomas Spencer has received research support from of the following sources: Shire Laboratories Inc, Cephalon, Eli Lilly & Company, Janssen, McNeil Pharmaceutical, Novartis Pharmaceuticals and the Department of Defense. In previous years, Dr Thomas Spencer has received research support from, has been a speaker for or on a speaker bureau or has been an Advisor or on an Advisory Board of the following sources: Shire Laboratories, Inc, Eli Lilly & Company, Glaxo-Smith Kline, Janssen Pharmaceutical, McNeil Pharmaceutical, Novartis Pharmaceuticals, Cephalon, Pfizer and the National Institute of Mental Health. Dr Spencer receives research support from Royalties and Licensing fees on copyrighted ADHD scales through MGH Corporate Sponsored Research and Licensing. Dr Spencer has a US Patent Application pending (Provisional Number 61/233686), through MGH corporate licensing, on a method to prevent stimulant abuse. Bertha K Madras, PhD, has the following financial interests: She is patent holder of 19 patents, including 11C- or 131I-altropane, other DAT imaging agents and DAT inhibitors, the majority of which are licensed to Alseres. Alseres licensed Altropane from Harvard University; Navidea Biopharmaceuticals, a radiopharmaceutical developer, is evaluating an option to license Altropane from Alseres. In the past year, she has received consulting fees from Prexa Pharmaceuticals, NIDA, research support from NIDA, has been an advisor to NIDA Council, CDC, and a non-reimbursed advisor to the Hilton Foundation and Convecta. In 2012, she received speaker fees from the following sources: McGill University, Dartmouth University, BOLD Coalition, Student Assistant Services and royalties as editor or author of four books, from Cold Spring Harbor Press, Neuroscience-Net, American Psychological Association. Joseph Biederman, MD is currently receiving research support from the following sources: Elminda, Janssen, McNeil, and Shire. In 2010, Dr Joseph Biederman did not receive any outside income. In 2009, Dr Joseph Biederman received a speaker’s fee from the following sources: Fundacion Areces, Medice Pharmaceuticals and the Spanish Child Psychiatry Association. In previous years, Dr Joseph Biederman received research support, consultation fees or speaker’s fees for/from the following additional sources: Abbott, Alza, AstraZeneca, Bristol Myers Squibb, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, Merck, NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc. and Wyeth. Yanli Zhang-James, MD, PhD, does not have any conflict of interest.

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Faraone, S., Spencer, T., Madras, B. et al. Functional effects of dopamine transporter gene genotypes on in vivo dopamine transporter functioning: a meta-analysis. Mol Psychiatry 19, 880–889 (2014). https://doi.org/10.1038/mp.2013.126

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