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.

Dopamine D4 receptor genotype variation in free-ranging rhesus macaques and its association with juvenile behavior

“…In humans, the polymorphism can include anywhere from 2 to 11 repeats (2R – 11R) (Ding et al 2002), with the 7R being the most derived allele. This DRD4 polymorphism has been shown to predict individual differences in impulsivity (Schilling et al 2014), risk-taking (Carpenter et al 2011), and novelty-seeking (Ebstein et al 1996) and has also been linked to clinical conditions such as Attention Deficit and Hyperactivity Disorder (ADHD; Tovo-Rodrigues et al 2013; Maitra et al 2014). …”

Child maltreatment, impulsivity, and antisocial behavior in African American children: Moderation effects from a cumulative dopaminergic gene index

“…Davis & Loxton, 2013). Presence of the del allele has been associated with addictive personality traits including impulsivity (Davis & Loxton, 2013), and the del/del genotype has been particularly associated with ADHD + Oppositional Defiant Disorder (Maitra et al, 2014). …”

Genetic influence alters the brain synchronism in perception and timing

“…Although the protein structure is not altered, it is thought that function is affected by regulating mRNA stability, transport and protein synthesis [ 47 ]. The functional alleles 10R and 9R alter the related phenotypes with planning and execution processes of working memory tasks, stimuli perception and increase the risk of neurological diseases [ 48 – 50 ] because of patients with a 9R allele exhibit less DAT activity than their homozygotes 10R. In the prefrontal cortex and caudate nucleus, and thus modulate dopamine levels in the CNS during the processing of temporal and cognitive information [ 51 , 52 ].…”