Abstract:
Objective The dopamine transporter gene (DAT1) is a critical component of the dopaminergic system and has been consistently
implicated in several neuropsychiatric diseases, but the disease mechanism remains elusive. Being multifactorial
with a genetic basis, the study aimed to find out the relationship between the DAT1 40 bp 3′UTR Variable Number Tandem
Repeat (VNTR) (rs28363170) and major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCH) in the
Pakistani population.
Methods In total, n = 1138 subjects, including MDD (n = 453), BD (n = 193), SHZ (n = 130), and healthy controls (n = 362),
were recruited for this study. The DAT1 40 bp 3′UTR VNTR was genotyped via the standard polymerase chain reaction
technique. The chi-squared (χ2) test with Yates’ continuity correction was applied to assess the association.
Results A statistically significant difference was observed in the genotype frequency analysis of 10R (χ² = 8.04, p = 0.018)
and 11R (χ² = 6.08, p = 0.04) with BD susceptibility however it did not remain significant after FDR correction. Whereas, in
SCH, significant genotype associations were observed for 10.5R (χ² = 10.18, p = 0.006) and 11R (χ² = 10.98, p = 0.004) with
the 11R allele demonstrating a significantly increased risk of SCH susceptibility (OR = 1.82, 95% CI: 1.31–2.54, p = 0.0004),
which remained significant after FDR correction. In addition, the 10.5R allele showed a statistically significant protective
association with suicidal behaviour (OR = 0.65 (95% CI: 0.47–0.91), p = 0.01), and significant risk associations with aggression
(OR = 1.75(95% CI: 1.27–2.40), p = 0.0006) and with insomnia. The presence of the 10R allele showed a significant risk
association (OR = 1.41 (95% CI: 1.11–1.80), p = 0.005).
Conclusion The present study indicated the variant-trait association of DAT1 40 bp 3′ UTR VNTR with psychiatric conditions
in the Pakistani population, suggesting disorder-specific and allele-dependent effects of DAT1 variation. Further largescale
studies, along with functional and integrative genomic analyses to understand the dynamics of DAT1, are required.
