A 40-bp VNTR polymorphism in the 3′-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism

Abstract

BackgroundADHD and alcoholism are psychiatric diseases with pathophysiology related to dopamine system. DAT1 belongs to the SLC6 family of transporters and is involved in the regulation of extracellular dopamine levels. A 40 bp variable number tandem repeat (VNTR) polymorphism in the 3′-untranslated region of DAT1/SLC6A3 gene was previously reported to be associated with various phenotypes involving disturbed regulation of dopaminergic neurotransmission.MethodsA total of 1312 subjects were included and genotyped for 40 bp VNTR polymorphism of DAT1/SLC6A3 gene in this study (441 alcoholics, 400 non-alcoholic controls, 218 ADHD children and 253 non ADHD children). Using miRBase software, we have performed a computer analysis of VNTR part of DAT1 gene for presence of miRNA binding sites.ResultsWe have found significant relationships between ADHD and the 40 bp VNTR polymorphisms of DAT1/SLC6A3 gene (P < 0.01). The 9/9 genotype appeared to reduce the risk of ADHD about 0.4-fold (p < 0.04). We also noted an occurrence of rare genotypes in ADHD (frequency different from controls at p < 0.01). No association between alcoholism and genotype frequencies of 40 bp VNTR polymorphism of DAT1/SLC6A3 gene has been detected.ConclusionsWe have found an association between 40 bp VNTR polymorphism of DAT1/SLC6A3 gene and ADHD in the Czech population; in a broad agreement with studies in other population samples. Furthermore, we detected rare genotypes 8/10, 7/10 and 10/11 present in ADHD boys only and identified miRNAs that should be looked at as potential novel targets in the research on ADHD.

Meta-Analysis Reveals Significant Association of the 3′-UTR VNTR inSLC6A3with Alcohol Dependence

“…Since Muramatsu et al (1995) first examined the association between SLC6A3 VNTR polymorphism and AD, many studies have been carried out (Sander et al, 1997, Ueno et al, 1999, Wernicke et al, 2002, Gorwood et al, 2003, Heinz et al, 2000, Kohnke et al, 2005, Le Strat et al, 2008, Bau et al, 2001, Chen et al, 2001, Dobashi et al, 1997, Ivashchenko et al, 2015, Mignini et al, 2012, Nedic Erjavec et al, 2014, Vasconcelos et al, 2015, Bhaskar et al, 2012, Sery et al, 2015, Foley et al, 2004, Wu et al, 2009), unfortunately with inconclusive results (van der Zwaluw et al, 2009). So far, there have been two meta-analyses (Xu and Lin, 2011, Du et al, 2011) regarding the association between SLC6A3 VNTR genotypes and alcoholism.…”

Noncoding RNA Regulation of Dopamine Signaling in Diseases of the Central Nervous System

“…Two separate studies investigated miRNA binding in polymorphic regions of the DAT gene. One study examined a 40-base pair 3′UTR region within the DAT transcript linked to Attention Deficit Hyperactivity Disorder (ADHD) (Sery et al, 2015). Bioinformatic analysis of this 40-base pair segment identified putative sites for miRs-1972, 30b-5p, 1301, and 6070 (Sery et al, 2015).…”

“…One study examined a 40-base pair 3′UTR region within the DAT transcript linked to Attention Deficit Hyperactivity Disorder (ADHD) (Sery et al, 2015). Bioinformatic analysis of this 40-base pair segment identified putative sites for miRs-1972, 30b-5p, 1301, and 6070 (Sery et al, 2015). A second study focused on a DAT polymorphism linked to bipolar disease, rs27072 (Pinsonneault et al, 2011).…”

miR-137 and miR-491 Negatively Regulate Dopamine Transporter Expression and Function in Neural Cells

“…Reuptake through the cell membrane that is mediated by the DA transporter (DAT) diminishes DA signaling in a sodium-dependent manner, and this plays a crucial role in maintaining DA homeostasis in neurons [2,9,10]. The gene encoding the DAT, solute carrier family 6 member 3 (SLC6A3), belongs to the SLC6 family of transporters [11,12]. The 3 0 untranslated region (UTR) of SLC6A3 mRNA contains a 40-bp tandem repeat, referred to as a variable-number tandem repeat (VNTR) polymorphism (rs28363170) [13], which can be present in 3-11 copies [11,14].…”