Significance of Dopaminergic Gene Variants in the Male Biasness of ADHD.

OBJECTIVE: ADHD is frequently detected in boys though there is no established cause. One possibility is that genes predisposing to ADHD have sexually dimorphic effects. With an aim to find out the reason for this male biasness, contribution of 14 functional polymorphisms was investigated in ADHD subjects. METHOD: Genomic DNA of probands, their parents, and ethnically matched controls was subjected to analysis of single-nucleotide polymorphisms and variable number of tandem repeats (VNTRs). RESULTS: Case-control analysis revealed significant higher occurrence of DAT1 intron 8 VNTR "5R" allele ( p = .028), DBH rs1108580 "A" allele ( p = .027), and MAOA-u VNTR-rs6323 3R-T haplotype ( p = .007) in male probands. Family-based analysis showed significant preferential transmission of Dopamine receptor D4 exon 3 VNTR-rs1800955 7R-T haplotype from parents to male probands ( p = .008). Interaction between DBH gene variants and low enzymatic activity was also noticed, especially in male probands. CONCLUSION: Data obtained may partly answer the male biasness of ADHD.

The Dopamine Receptor D5 May Influence Age of Onset: An Exploratory Study on Indo-Caucasoid ADHD Subjects.

The objective was to investigate contribution of the dopamine receptor 5 (DRD5) gene variants in the symptoms of attention-deficit/hyperactivity disorder (ADHD) probands since brain regions identified to be affected in these group of patients have higher expression of the DRD5 receptor. Out of 22 exonic variants, 19 were monomorphic in the Indo-Caucasoid individuals. rs6283 "C" and rs113828117 "A" exhibited significant higher occurrence in families with ADHD probands. Several haplotypes showed biased occurrence in the probands. Early and late onset groups exhibited significantly different genotypic frequencies. A new G>A substitution was observed in the control samples only. The late onset group exhibited higher scores for hyperactivity as compared to the early onset group. The authors infer that the age of onset of ADHD may at least partially be affected by DRD5 variants warranting further investigation on the role of DRD5 in the disease etiology.

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

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.

Catecholaminergic gene variants: contribution in ADHD and associated comorbid attributes in the eastern Indian probands.

Contribution of genes in attention deficit hyperactivity disorder (ADHD) has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273), DRD2 (rs1800496, rs1801028, and rs1799732), DRD4 (rs4646984 and rs4646983), and COMT (rs165599 and rs740603) in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N = 170), their parents (N = 310), and ethnically matched controls (n = 180) was used for genotyping followed by population- and family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by case-control analysis, while DDC and COMT exhibited bias in familial transmission (P < 0.05). rs3837091 "AGAG," rs3735273 "A," rs1799732 "C," rs740603 "G," rs165599 "G" and single repeat alleles of rs4646984/rs4646983 showed positive correlation with co-morbid characteristics (P < 0.05). Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P < 0.001), while family-based data showed interaction between DDC and DRD2 (P = 0.04). This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD.

Role of SNAP25 explored in eastern Indian attention deficit hyperactivity disorder probands.

Synaptosomal-associated protein 25 (SNAP25) is an essential component for synaptic vesicle mediated release of neurotransmitters. Deficiencies or abnormal structure or function of SNAP25 protein, possibly arising through genetic variations in the relevant DNA code, has been suggested to play role in the pathology of several neurobehavioural disorders including Attention deficit Hyperactivity Disorder (ADHD) and a number of polymorphisms in the SNAP25 gene has been studied for association with the disorder. In the present investigation, for the first time association between ADHD and six SNAP25 polymorphisms, rs1889189, rs362569, rs362988, rs3746544, rs1051312, and rs8636 was explored in eastern Indian population. Subjects were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV. Genomic DNA isolated from peripheral blood leukocytes of ADHD probands (n = 150), their parents (n = 272) and ethnically matched controls (n = 100) was used for amplifying target sites. Data obtained were subjected to population- as well as family-based analyses. While case-control analysis revealed lack of any significant difference for alleles, family-based studies revealed a mild over transmission rs3746544 'T' and rs8636 'C' alleles (P = 0.05 and 0.03 respectively). Haplotypes formed between rs362569 "T", 362988 "G", rs3746544 "T", rs1051312 "T" and rs8636 "C" in different combinations showed statistically significant transmission to ADHD probands. Excepting rs3746544 and rs8636, all the tested sites showed very low linkage disequilibrium between them. Data obtained in this preliminary study indicates that rs3746544 'T' allele may have some role in the disease etiology in the studied Indian population.

Importance of gene variants and co-factors of folate metabolic pathway in the etiology of idiopathic intellectual disability.

Different components of the folate metabolic cycle are crucial for maintaining integrity of DNA. The present study was aimed at exploring the role of some important constituents of the folate cycle in the etiology of idiopathic intellectual disability (IID). Nuclear families with IID probands (n=226) and ethnically matched controls (n=181) were recruited for micronucleus, karyotype, genetic polymorphism (MTR rs1805087, MTRR rs1801394, and DHFR rs70991108), folate, vitamin B6, vitamin B12, and cysteine analysis. Significant difference in genotype frequencies in IID probands and their parents were observed for rs1805087 (P=0.03, 0.02), rs1801394 (P=0.03, 0.001), and rs70991108 ((P=0.03, 0.02) as compared to controls. IID probands showed significantly higher micronucleus frequency (P=0.01) and decreased vitamin B6 level (P=0.002). A strong correlation between rs1801394 'G' allele and micronucleus was also noticed. From the present investigation, a role of genetic polymorphisms and vitamin B6 levels could be hypothesized in the etiology of IID.

Role of gene-gene/gene-environment interaction in the etiology of eastern Indian ADHD probands.

Associations between attention deficit hyperactivity disorder (ADHD) and genetic polymorphisms in the dopamine receptors, transporter and metabolizing enzymes have been reported in different ethnic groups. Gene variants may affect disease outcome by acting synergistically or antagonistically and thus their combined effect becomes an important aspect to study in the disease etiology. In the present investigation, interaction between ten functional polymorphisms in DRD4, DAT1, MAOA, COMT, and DBH genes were explored in the Indo-Caucasoid population. ADHD cases were recruited based on DSM-IV criteria. Peripheral blood samples were collected from ADHD probands (N=126), their parents (N=233) and controls (N=96) after obtaining informed written consent for participation. Genomic DNA was subjected to PCR based analysis of single nucleotide polymorphisms and variable number of tandem repeats (VNTRs). Data obtained was examined for population as well as family-based association analyses. While case-control analysis revealed higher occurrence of DAT1 intron 8 VNTR 5R allele (P=0.02) in cases, significant preferential transmission of the 7R-T (DRD4 exon3 VNTR-rs1800955) and 3R-T (MAOA-u VNTR-rs6323) haplotypes were noticed from parents to probands (P=0.02 and 0.002 respectively). Gene-gene interaction analysis revealed significant additive effect of DBH rs1108580 and DRD4 rs1800955 with significant main effects of DRD4 exon3 VNTR, DAT1 3'UTR and intron 8 VNTR, MAOA u-VNTR, rs6323, COMT rs4680, rs362204, DBH rs1611115 and rs1108580 thereby pointing towards a strong association of these markers with ADHD. Correlation between gene variants, high ADHD score and low DBH enzymatic activity was also noticed, especially in male probands. From these observations, an impact of the studied sites on the disease etiology could be speculated in this ethnic group.

Study on DBH genetic polymorphisms and plasma activity in attention deficit hyperactivity disorder patients from Eastern India.

Dysfunctions in the norepinephric pathway have been speculated in the etiology of attention deficit hyperactivity disorder (ADHD), a common problem for children. Synthesis of norepinephrine from dopamine is catalyzed by the enzyme dopamine beta-hydroxylase and numerous polymorphisms in the DBH gene have been found to exert their direct influence on the enzyme activity independently. In the present study association of ADHD with four genetic polymorphisms, DBH-STR, rs1611115, rs1108580, and rs2519152, was examined in subjects belonging to eastern India. ADHD subjects (n = 111) were recruited following DSM-IV criteria. Peripheral blood samples were collected from nuclear families with ADHD probands. A group of ethnically matched healthy volunteers (n = 130) was also recruited. Genomic DNA was analyzed by PCR amplification followed by restriction digestion and genotyping. Data obtained were subjected to both family-based as well as population-based statistical analyses. Plasma DbetaH activity was measured using a photometric assay and its correlation with the genetic polymorphisms was analyzed using analysis of variance. Case-control analysis revealed no significant differences in allelic frequencies; however, significant paternal over-transmission (P = 0.02) of the rs2519152 'G' allele to ADHD probands was noticed. A haplotype, composed of 12R-C-G-G, also showed biased transmission. Strong correlation was observed between enzyme activity and rs1611115, rs1108580, and rs2519152 (P = 1.51E-6, 0.04, and 0.003, respectively). The present study hints toward the fact that DBH gene polymorphisms have some role in the etiology of ADHD in eastern Indian population and their study could be useful for therapeutic intervention.