Association of the dopamine transporter gene (DAT1) core promoter polymorphism −67T variant with schizophrenia

Abstract

Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of schizophrenia. The dopamine transporter (DAT1) mediates the active reuptake of dopamine from the synapses and thereby plays a key role in the regulation of the dopaminergic neurotransmission. In this study, we sought to determine the possible association of the DAT1 gene core promoter polymorphism -67A/T with schizophrenia in a case/control study. The allele and genotype frequencies of the polymorphism were studied in 100 patients and 100 controls, which were matched on the basis of sex, age, and ethnicity. The genotype frequencies in the patients group were as follows: AA 29%; AT 59%; TT 12% versus the genotype frequencies in the control group: AA 57%; AT 38%; TT 5% [chi2 = 16.54, df = 2, OR = 2.25 (95% CI 1.46-3.45, P < or = 0.0003]. For the first time, these findings provide tentative evidence for the contribution of the DAT1 gene core promoter polymorphism to the etiopathophysiology of schizophrenia at least in the Iranian male population that we studied. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings.

Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples

“…6,19 However, the 'T' variant of this SNP was recently observed to be associated with schizophrenia in a sample of Iranian males. 20 It is this variant that was observed to increase DAT1 gene expression twofold in our functional analyses. 18 Thus, it is possible that increased levels of expression of DAT1 driven by variation in the core promoter of this gene contribute a predisposition to psychiatric illness.…”

“…Association studies have implicated variants of this VNTR in the causation of several psychiatric disorders, most notably ADHD. [1][2][3]20,21 Functional analyses of the two most common variants, the 10-and 9-repeat alleles have, however, been somewhat contradictory with different groups reaching different conclusions about which of these two alleles is associated with increased DAT gene expression. [22][23][24][25][26][27] In our previous studies, we found no evidence that either of the common alleles had any effect on DAT gene expression, nor did we find evidence for an association of this VNTR to bipolar disorder.…”

Lack of association between the −839C/T polymorphism in the SLC6A3 gene promoter and schizophrenia in the Iranian population

“…Moreover, a family-based study demonstrated potential association between these markers and schizophrenia (Stober et al 2005). Recently, a case-control study was performed in an Iranian population that showed an association between the -67A/T SNP and schizophrenia (Khodayari et al 2004). Therefore, because of the importance of the 5 -flanking region of the SLC6A3 gene in the etiology of schizophrenia (Stober et al 2005), we first conducted the potential association study between schizophrenia and the -839 C/T SNP in an Iranian ethnic group.…”

LeuT: A prokaryotic stepping stone on the way to a eukaryotic neurotransmitter transporter structure

“…SLC6 members, also known as neurotransmitter sodium symporters (NSS), have garnered significant attention because their dysfunction has been implicated in multiple debilitating central and peripheral nervous system diseases, including depression, 5 anxiety, 5 autism, 6 epilepsy, 7 attention deficit hyperactivity disorder (ADHD), 8 obsessive-compulsive disorder (OCD), [9][10][11] orthostatic intolerance, 12 X-linked creatine deficiency syndrome 13 and, to a lesser extent, bipolar disorder, 14 schizophrenia, 15,16 Parkinson's disease 5 and Tourette's syndrome. 17 Notably, these molecular machines are the target of therapeutic agents such as antidepressants, 18 anticonvulsants 19 and some psychostimulants 8 as well as deleterious substances such as cocaine and amphetamines.…”