ADHDgene Database

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Large-scale studies

Data Summary

Published Variant
- SNP: 1391
- CNV: 398
- Others: 173
Published Gene: 359
Published Region: 128
Pathway by PBA: 8
Study: 361

Study Report

Basic Info

Reference	Das M, 201121216270
Citation	Das M., Das Bhowmik A., Bhaduri N., Sarkar K., Ghosh P., Sinha S., Ray A., Chatterjee A. and Mukhopadhyay K. (2011) "Role of gene-gene/gene-environment interaction in the etiology of eastern Indian ADHD probands." Prog Neuropsychopharmacol Biol Psychiatry, 35(2): 577-87.
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	126 ADHD children and their parents; 96 controls
Predominant Ethnicity	Indo-Caucasian
Population	India
Gender	male to female ratio: 10:1 of cases, 10:3 of controls
Age Group	Children/Adolescents and Adults : case: 4.5-13 years (mean=7.28, SD=2.67); control: 5-30 years (mean=19.5, SD=8.74)

Detail Info

Summary	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. 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.
Total Sample	ADHD cases (N=126), comprising of 109 parent-offspring trios and 15 duos (one parent absent) and two affected probands, were recruited. Control subjects (N=96) employed for genetic analyses were also evaluated using similar psychometric procedure and comprised of healthy volunteerswith an age range of 5-30 years and 10:3male:female ratio. Recruited individuals all belonged to Indo-Caucasoid ethnic group from the eastern Indian state of West Bengal.
Sample Collection	ADHD cases were recruited from the out-patient department of Manovikas Kendra, Kolkata, India.
Diagnosis Description	fulfillment of DSM-IV (APA, 1994) diagnostic criteria and hyperactivity-inattention level>12 assessed by the Conners' Parents and Teachers Rating Scale (Conners et al., 1998);
Technique	Peripheral blood was collected from all the participants and processed for extraction of genomic DNA (Miller et al., 1998). 75-100 ng of genomic DNA was used for PCR amplification in Perkin Elmer thermal cycler (Gene Amp #2400).
Analysis Method	Association studies were performed using the UNPHASED program version 2.404. The program COCAPHASE was used to compare the allele frequencies of individual markers. Transmission Disequilibrium Test (TDT) analysis was used to perform family-based association study using the program TDTPHASE. Combined effect of two polymorphisms in each gene was also examined by haplotype analysis using the UNPHASED program. Evaluation of gene-gene interactions with case-control dataset was performed by the Multifactor Dimentionality Reduction (MDR) program. PIFACE version 1.72 was used to evaluate power of the generic chi-square tests (case-control and TDT) and MDR analysis at 5% and 2.5% significance level (after Bonferroni correction) respectively. Evaluated powers were also checked for reproducibility using the Genetic Power Calculator software assuming prevalence of ADHD as 0.03.
Result Description	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.

SNPs reported by this study (count: 6)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs4680	G/A		ETDT P-value=0.83, X²(1df)=0.04, RR=1; allelic frequencies COCAPHASE P-value=0.7, X²=0.15 for G; ETDT P-value=0.83, X²(1df)=0.04, RR=0.96; allelic frequencies COCAPHASE P-value=0.7, X²=0.15 for A	both case-control and family-based analysis failed to show a...... both case-control and family-based analysis failed to show any significant impact More...	Non-significant
rs6323	G/T		ETDT P-value=0.35, X²(1df)=0.86, RR=1; allelic frequencies COCAPHASE P-value=0.82, X²=0.05 for G; ETDT P-value=0.35, X²(1df)=0.86, RR=1.33; allelic frequencies COCAPHASE P-value=0.82, X²=0.05 for T	frequency of G allele was higher in both cases and controls ...... frequency of G allele was higher in both cases and controls as compared to the T; familial analysis revealed a mild bias in T allele transmission More...	Non-significant
rs1800955	T/G		ETDT P-value=0.32, X²(1df)=1.002, RR=1; allelic frequencies COCAPHASE P-value=0.56, X²=0.34 for T; ETDT P-value=0.32, X²(1df)=1.002, RR=0.8; allelic frequencies COCAPHASE P-value=0.56, X²=0.34 for C	no significant contribution was noticed by either case-contr...... no significant contribution was noticed by either case-control or family-based analysis More...	Non-significant
rs1108580	G/A		ETDT P-value=0.25, X²(1df)=1.33, RR=1; allelic frequencies COCAPHASE P-value=0.08, X²=3.08 for G; ETDT P-value=0.25, X²(1df)=1.33, RR=0.75; allelic frequencies COCAPHASE P-value=0.08, X²=3.08 for A	no significant association was noticed by case-control or fa...... no significant association was noticed by case-control or family-based association analyses More...	Non-significant
rs362204	C/Del		ETDT P-value=0.31, X²(1df)=1.03, RR=1; allelic frequencies COCAPHASE P-value=0.84, X²=0.04 for C; ETDT P-value=0.31, X²(1df)=1.03, RR=1.26; allelic frequencies COCAPHASE P-value=0.84, X²=0.04 for Del	both case-control and family-based analysis failed to show a...... both case-control and family-based analysis failed to show any significant impact More...	Non-significant
rs1611115	C/T		ETDT P-value=0.49, X²(1df)=0.47, RR=1; allelic frequencies COCAPHASE P-value=0.09, X²=2.8 for C; ETDT P-value=0.49, X²(1df)=0.47, RR=0.83; allelic frequencies COCAPHASE P-value=0.09, X²=2.8 for T	no significant association was noticed by case-control or fa...... no significant association was noticed by case-control or family-based association analyses More...	Non-significant

Other variant reported by this study (count: 4)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
SLC6A3 intron8 VNTR			ETDT P-value=0.1, X²(1df)=2.77, RR=7.71e+007; all...... ETDT P-value=0.1, X²(1df)=2.77, RR=7.71e+007; allelic frequencies COCAPHASE P-value=0.8, X²=0.07 for 11R; ETDT P-value=0.53, X²(1df)=0.4, RR=0.53; allelic frequencies COCAPHASE P-value=0.056, X²=3.64 for 10R; ETDT P-value=0.31, X²(1df)=1.02, RR=1.8; allelic frequencies COCAPHASE P-value=0.28, X²=1.17 for 9R; ETDT P-value=0.34, X²(1df)=0.89, RR=0.81; allelic frequencies COCAPHASE P-value=0.002, X²=9.59 for 6R; ETDT P-value=0.53, X²(1df)=0.4, RR=1; allelic frequencies COCAPHASE P-value=0.02, X²=5.49 for 5R; allelic frequencies COCAPHASE P-value=0.29, X²=1.13 for 7R More...	the data was statistically not significant in either case-control or family-based analysis for 11R, 10R, 9R and 7R; the 6R allele showed significantly lower frequency in ADHD case group but ETDT analysis failed to show any bias in transmission; the 5R allele showed significantly higher occurrence in ADHD case group but ETDT analysis failed to show any bias in transmission	Significant
SLC6A3 3'-UTR VNTR			ETDT P-value=1, X²(1df)=0, RR=1; allelic frequenc...... ETDT P-value=1, X²(1df)=0, RR=1; allelic frequencies COCAPHASE P-value=0.99, X²=0.0001 for 11R; ETDT P-value=0.08, X²(1df)=3.1, RR=0.84; allelic frequencies COCAPHASE P-value=0.34, X²=0.92 for 10R; ETDT P-value=0.14, X²(1df)=2.19, RR=1.35; allelic frequencies COCAPHASE P-value=0.61, X²=0.26 for 9R; ETDT P-value=1, X²(1df)=0, RR=0.85; allelic frequencies COCAPHASE P-value=0.83, X²=0.04 for 8R; ETDT P-value=0.25, X²(1df)=1.33, RR=2.25; allelic frequencies COCAPHASE P-value=0.02, X²=5.6 for 7R More...	the data was statistically not significant in either case-control or family-based analysis for 8R, 9R, 10R and 11R; no significant contribution was noticed by family-based analysis; case-control analysis revealed statistically significant difference for the 7R	Significant
MAOA promoter VNTR			ETDT P-value=0.63, X²(1df)=0.23, RR=1; allelic fr...... ETDT P-value=0.63, X²(1df)=0.23, RR=1; allelic frequencies COCAPHASE P-value=0.57, X²=0.33 for 3R; ETDT P-value=0.63, X²(1df)=0.23, RR=0.86; allelic frequencies COCAPHASE P-value=0.57, X²=0.33 for 4R More...	the data was statistically not significant in either case-control or family-based analysis	Non-significant
DRD4 exon3 VNTR	2-7R		ETDT P-value=0.7, X²(1df)=0.14, RR=1; allelic fre...... ETDT P-value=0.7, X²(1df)=0.14, RR=1; allelic frequencies COCAPHASE P-value=0.83, X²=0.04 for 2R. ETDT P-value=1, X²(1df)=0, RR=1.1; allelic frequencies COCAPHASE P-value=0.81, X²=0.06 for 3R. ETDT P-value=0.47, X²(1df)=0.51, RR=1.1; allelic frequencies COCAPHASE P-value=0.92, X²=0.008 for 4R. ETDT P-value=0.31, X²(1df)=1.05, RR=0.42; allelic frequencies COCAPHASE P-value=0.38, X²=0.77 for 5R. ETDT P-value=0.1, X²(1df)=2.64, RR=2.27; allelic frequencies COCAPHASE P-value=0.16, X²=2.01 for 6R. ETDT P-value=0.41, X²(1df)=0.68, RR=2.22; allelic frequencies COCAPHASE P-value=0.55, X²=0.35 for 7R. More...	no significant contribution was noticed by either case-control or family-based analysis for 2-5R; no significant contribution was noticed by case-control analysis; ETDT analysis revealed higher transmission from parents to ADHD probands with higher relative risk for 6R and 7R.	Non-significant

Genes reported by this study (count: 5)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
SLC6A3	minimum UNPHASED P-value=0.002, X²=9.33 for 10R-6...... minimum UNPHASED P-value=0.002, X²=9.33 for 10R-6R haplotype frequencies in the case-control analysis, which showed that the 10R-6R haplotype was significantly higher in controls; minimum ETDT P-value=0.09 showed no significant over transmission of any haplotypes More...	Significant
DBH	minimum UNPHASED P-value=0.0009, X²=10.9 revealed...... minimum UNPHASED P-value=0.0009, X²=10.9 revealed lower occurrence of T-G haplotypes in the ADHD cases; minimum ETDT P-value=0.22 showed no significant over transmission of any haplotypes More...	Significant
DRD4	minimum UNPHASED P-value=0.29 for haplotype frequencies in t...... minimum UNPHASED P-value=0.29 for haplotype frequencies in the case-control analysis showed no significant difference; minimum ETDT P-value=0.02, X²(1df)=5.54, RR=5.18e+008, which showed significant over transmission of the 7R-T haplotypes from parents More...	Significant
COMT	minimum UNPHASED P-value=0.71 for haplotype frequencies in t...... minimum UNPHASED P-value=0.71 for haplotype frequencies in the case-control analysis and minimum ETDT P-value=0.47, none of the haplotypes showed any significant association More...	Non-significant
MAOA	minimum UNPHASED P-value=0.06 for haplotype frequencies in t...... minimum UNPHASED P-value=0.06 for haplotype frequencies in the case-control analysis and minimum ETDT P-value=0.002, X²(1df)=9.7, RR=8.06e+007 in the family-based analysis; COCAPHASE showed a bias in the occurrence of 3R-T haplotype in the ADHD probands supported by significant higher transmission of the haplotype More...	Significant