Dopamine Transporter Gene Variant Affecting Expression in Human Brain is Associated with Bipolar Disorder
Open accessAbstract
The gene encoding the dopamine transporter (DAT) has been implicated in CNS disorders, but the responsible polymorphisms remain uncertain. To search for regulatory polymorphisms, we measured allelic DAT mRNA expression in substantia nigra of human autopsy brain tissues, using two marker SNPs (rs6347 in exon 9 and rs27072 in the 3'-UTR). Allelic mRNA expression imbalance (AEI), an indicator of cis-acting regulatory polymorphisms, was observed in all tissues heterozygous for either of the two marker SNPs. SNP scanning of the DAT locus with AEI ratios as the phenotype, followed by in vitro molecular genetics studies, demonstrated that rs27072 C>T affects mRNA expression and translation. Expression of the minor T allele was dynamically regulated in transfected cell cultures, possibly involving microRNA interactions. Both rs6347 and rs3836790 (intron8 5/6 VNTR) also seemed to affect DAT expression, but not the commonly tested 9/10 VNTR in the 3'UTR (rs28363170). All four polymorphisms (rs6347, intron8 5/6 VNTR, rs27072 and 3'UTR 9/10 VNTR) were genotyped in clinical cohorts, representing schizophrenia, bipolar disorder, depression, and controls. Only rs27072 was significantly associated with bipolar disorder (OR = 2.1, p = 0.03). This result was replicated in a second bipolar/control population (OR = 1.65, p = 0.01), supporting a critical role for DAT regulation in bipolar disorder.
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A SNP associated with increased DAT1 expression is predictive of higher brain atrophy and associated with increased dementia.
“Interestingly, a SNP associated with increased DAT1 expression (30) is predictive of higher brain atrophy and associated with increased dementia (31).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [30]
LDX increased pro-inflammatory cytokines TNFα and IL-6, and also anti-inflammatory cytokines IL-4 and IL-10 in the frontal cortex, striatum and serum in animal models of bipolar disorder.
“It has been assessed in ADHD comorbid disease, such as bipolar disorder in animal models [160], in which LDX increased the pro-inflammatory cytokines TNFα and IL-6, and also the anti-inflammatory cytokines IL-4 and IL-10 in the frontal cortex, striatum and serum [160, 198].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [198]
The Clinical Association Analyses section describes genotyping human subjects with bipolar disorder, schizophrenia, and matched controls. Our copy contains no passage addressing LDX treatment or its effects on TNFα, IL-6, IL-4, or IL-10 in animal models; searches for those terms and for inflammatory cytokines found none. (LLM, conf=0.76)
Experimental — accuracy not yet measuredLDX promotes the activation of pro-inflammatory cytokines such as TNFα and IL-6, although it also promotes the expression of the anti-inflammatory cytokines IL-4 and IL-10 in the frontal cortex, striatum and serum.
“LDX promotes the activation of pro-inflammatory cytokines such as TNFα and IL-6, although it also promotes the expression of the anti-inflammatory cytokines IL-4 and IL-10 in the frontal cortex, striatum and serum.”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [198]
The 3′ UTR reporter-assay and Clinical Association Analyses passages concern dopamine transporter gene variants, not LDX or cytokine expression. Searches for LDX, TNFα, IL-6, IL-4, IL-10, and inflammatory cytokines found no passage in our copy addressing the claim; page numbers were not available. (LLM, conf=0.78)
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References 42 · Cited by 147
Research works printed but not linked: 1
- First M, Spitzer R, Williams J, Gibbon M (1998). Structured Clinical Interview for Axis I DSM IV Disorders, Patient Edition (SCIDI/P, Version2.0) edn. Biometric Research Department: New York.
- Authors
- Pinsonneault, J. K., Han, D. D., Burdick, K. E., Kataki, M., Bertolino, A., Malhotra, A. K., Gu, H. H., & Sadee, W.
- Affiliations
- The Ohio State University (US)
- Albert Einstein College of Medicine (US)
- University of Bari Aldo Moro (IT)
- Corresponding author
- Pinsonneault, Julia K
- Venue
- Neuropsychopharmacology
- Published
- 2011-04-27
- Volume
- 36
- Issue
- 8
- Pages
- 1644-1655
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3138671
- OpenAlex
- W1988592652
- Cited by
- 147
- References
- 42
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 11 · 2021: 7 · 2020: 11 · 2019: 6 · 2018: 10 · 2017: 9 · 2016: 10 · 2015: 16 · 2014: 13 · 2013: 15 · 2012: 10
- FWCI
- 9.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Funders
- Ohio State University
- National Institutes of Health
- National Institute on Drug Abuse (DA022199, DA 014610, R01DA014610, R21DA018744, R01DA022199)
- National Institute of General Medical Sciences (U01GM092655, GM092655)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- dopamine transporter, bipolar disorder, regulatory polymorphisms, allelic expression imbalance, 3'UTR polymorphism, VNTR polymorphism, substantia nigra, mRNA expression, microRNA, schizophrenia, depression, genetic association
- MeSH terms
- Aged, Aged, 80 and over, Animals, Bipolar Disorder, Brain, Cricetulus, Gene Expression Regulation, Cricetinae, Haplotypes, Humans, Middle Aged, Genetic Variation, Cohort Studies, CHO Cells, Polymorphism, Single Nucleotide, Dopamine Plasma Membrane Transport Proteins, Genome-Wide Association Study
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