Potential contribution of dopaminergic gene variants in ADHD core traits and co-morbidity: a study on eastern Indian probands

Abstract

Association of dopaminergic genes, mainly receptors and transporters, with Attention Deficit Hyperactivity Disorder (ADHD) has been investigated throughout the world due to the importance of dopamine (DA) in various physiological functions including attention, cognition and motor activity, traits. However, till date, etiology of ADHD remains unknown. We explored association of functional variants in the DA receptor 2 (rs1799732 and rs6278), receptor 4 (exon 3 VNTR and rs914655), and transporter (rs28363170 and rs3836790) with hyperactivity, cognitive deficit, and co-morbid disorders in eastern Indian probands. Diagnostic and Statistical Manual for Mental Disorders-IV was followed for recruitment of nuclear families with ADHD probands (N = 160) and ethnically matched controls (N = 160). Cognitive deficit and hyperactive traits were measured using Conner's parents/teachers rating scale. Peripheral blood was collected after obtaining informed written consent and used for genomic DNA isolation. Genetic polymorphisms were analyzed by PCR-based methods followed by population- as well as family-based statistical analyses. Association between genotypes and cognitive/hyperactivity traits and co-morbidities was analyzed by the Multifactor dimensionality reduction (MDR) software. Case-control analysis showed statistically significant difference for rs6278 and rs28363170 (P = 0.004 and 1.332e-007 respectively) while family-based analysis exhibited preferential paternal transmission of rs28363170 '9R' allele (P = 0.04). MDR analyses revealed independent effects of rs1799732, rs6278, rs914655, and rs3836790 in ADHD. Significant independent effects of different sites on cognitive/hyperactivity traits and co-morbid disorders were also noticed. It can be summarized from the present investigation that these gene variants may influence cognitive/hyperactive traits, thereby affecting the disease etiology and associated co-morbid features.

Fig. 1

Frequency of probands exhibiting different levels of ADHD index

Fig. 2

Correlation of ADHD index with cognitive deficit and hyperactive traits

Fig. 3

Gene–gene interaction analyzed using case–control data in ADHD cases (a), considering cognitive deficit (b) and hyperactivity (c) as endophenotypes. All the positive IG values in the nodes indicate independent main effect of all the markers. All the lines with negative IG values indicate redundancy or lack of any synergistic interaction between the markers. Nodal No. 1—DRD2 rs1799732, 2—DRD2 rs6278, 3—DRD4 ex 3, 4—DRD4 rs914655, 5—SLC6A3 rs28363170, 6—SLC6A3 rs3836790, P—endophenotypes (cognitive deficit/hyperactivity)

Fig. 4

Gene–gene interaction analyzed in ADHD cases exhibiting co-morbid a LD, b MD, c ODD, and d CD using case–control data. All the positive IG values in the nodes indicate independent main effect of all the markers. All the lines with negative IG values indicate redundancy or lack of any synergistic interaction between the markers. Nodal No. 1—DRD2 rs1799732, 2—DRD2 rs6278, 3—DRD4 ex 3, 4—DRD4 rs914655, 5—SLC6A3 rs28363170, and 6—SLC6A3 rs3836790