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

Detail ...

Study Report

Basic Info

Reference	Ribases M, 2009(b)17938636
Citation	Ribases M., Ramos-Quiroga J. A., Hervas A., Bosch R., Bielsa A., Gastaminza X., Artigas J., Rodriguez-Ben S., Estivill X., Casas M., Cormand B. and Bayes M. (2009) "Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB." Mol Psychiatry, 14(1): 71-85.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	451 ADHD patients (188 adults and 263 children) and 400 controls
Predominant Ethnicity	Caucasian
Population	Spain
Gender	78% of patients were males (72.8% of adults and 82.1% of children)
Age Group	Children/Adolescents and Adults : mean age 29.86 years (SD=11.86) for adult ADHD patients, 9.18 years (SD=2.56) for child ADHD patients and 42.38 years (SD=13.6) for the controls.

Detail Info

Summary	This study aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood and childhood ADHD; (2) the MAOB gene was found specifically associated in the adult ADHD sample and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults and children. The data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.
Total Sample	451 ADHD patients (188 adults and 263 children) and 400 controls
Sample Collection	All ADHD patients and control samples are Caucasoid
Diagnosis Description	All patients met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria for ADHD and consisted of 188 adult cases (67% combined ADHD, 29.3% inattentive ADHD and 3.7% hyperactive- impulsive ADHD patients) and 263 children (73% combined ADHD, 22% inattentive ADHD and 5% hyperactive-impulsive ADHD patients). Diagnosis was blind to genotype. The control sample, consisting of 400 Caucasoid-unrelated adult subjects in whom DSM-IV ADHD symptoms have been excluded retrospectively, matched for sex the ADHD clinical group. For detailed information about clinical assessment of adulthood and childhood ADHD, please refer to the original publication.
Technique	Genomic DNA was isolated from peripheral blood lymphocytes by the salting-out procedure or using magnetic bead technology with the Chemagic Magnetic Separation Module I and the Chemagic DNA kit, according to the manufacturer's recommendations (Chemagen AG, Baesweiler, Germany). The doublestranded DNA concentrations of all samples were determined on a Gemini XPS fluorometer (Molecular Devices, Sunnyvale, CA, USA) using the PicoGreen dsDNA Quantitation Kit (Molecular Probes, Eugene, OR, USA), following the manufacturer's instructions. 19 candidate genes involved in the serotoninergic neurotransmission pathway were selected. A total of 129 tagSNPs (69 in multi-loci bins and 60 singletons) were chosen . Three additional SNPs located within exons were included in the analysis. The 132 selected SNPs were assessed with the automated assay design pipeline at ms.appliedbiosystems.com/snplex/snplexStart.jsp. Two SNPlex genotyping assays of 47 and 48 SNPs were designed, 27 SNPs were included in two other assays with additional SNPs not related to this project and a proper design could not be achieved for 10 SNPs, which translates into a design rate of 92.4%. To detect population stratification, 48 unlinked anonymous SNPs located at least 100 kb distant from known genes were also genotyped. All SNPs were genotyped using the SNPlex platform (Applied Biosystems, Foster City, CA, USA) as described. For more details, please refer to the original publication.
Analysis Method	First both clinical samples were analyzed independently. Then, and only when a potential common susceptibility factor was identified, the two data sets were analyzed together. ADHD patients were also subdivided into two main diagnostic groups, combined ADHD and inattentive ADHD. The hyperactive-impulsive ADHD group could not be considered due to its small sample size (n = 20). The analysis of minimal statistical power was performed post hoc using the Genetic Power Calculator software, assuming an odds ratio (OR) of 1.5, prevalence of 0.05, significance level of 0.05 and the lowest MAF of 0.153. Potential genetic stratification was tested by analyzing the SNPs in Hardy-Weinberg equilibrium from the 48 anonymous SNP set with three different approaches: (1) the STRUCTURE software; (2) the Fst coefficient and (3) the method by Pritchard and Rosenberg. As ADHD children were collected by three clinical groups, genetic heterogeneity among them was evaluated by comparing allele frequencies of the 88 autosomic SNPs included in the case-control study using X² tests with the statistical package SPSS 12.0. For details about single-marker and multiple-marker analysis, please refer to the original publication.
Result Description	Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P-value=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P-value=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P-value=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P-value=0.0036; OR=1.63) and children (P-value=0.0084; OR=1.49). For more details, please refer to the original publication.

SNPs reported by this study (count: 26)

SNP	Statistical Values	Author Comments	Result of Statistical Analysis
rs7984966	Case-control test: lowest P-value=0.05 for genotype analysis, P-value=0.024 for allele analysis in all adult ADHD; lowest P-value=0.0012 for genotype analysis, P-value=0.0019 for allele analysis in adult combined ADHD. \| lowest P-value=0.033 for genotype analysis, P-value=0.039 for allele analysis in all childhood ADHD; lowest P-value=0.0097 for genotype analysis, P-value=0.011 for allele analysis in childhood combined ADHD.	Still significant associated with adult combined ADHD after ...... Still significant associated with adult combined ADHD after correcting for multiple comparisons More...	Significant
rs7322347	Case-control test: lowest P-value=0.03 for genotype analysis, P-value=0.3 for allele analysis in all adult ADHD; lowest P-value=0.014 for genotype analysis, P-value=0.13 for allele analysis in adult combined ADHD. \| lowest P-value=0.018 for genotype analysis, P-value=0.0085 for allele analysis in all childhood ADHD; lowest P-value=0.0053 for genotype analysis, P-value=0.0015 for allele analysis in childhood combined ADHD.	Still significant associated with childhood combined ADHD af...... Still significant associated with childhood combined ADHD after correcting for multiple comparisons More...	Significant
rs6944090	Case-control test: lowest P-value=0.025 for genotype analysis, P-value=0.077 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs676643	Case-control test: lowest P-value=0.054 for genotype analysis, P-value=0.045 for allele analysis in childhood inattentive ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs9659997	Case-control test: lowest P-value=0.023 for genotype analysis, P-value=0.0055 for allele analysis in all adult ADHD; lowest P-value=0.028 for genotype analysis, P-value=0.031 for allele analysis in adult inattentive ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs9534495	Case-control test: lowest P-value=0.042 for genotype analysis, P-value=0.043 for allele analysis in all adult ADHD; lowest P-value=0.0079 for genotype analysis, P-value=0.0054 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs7997012	Case-control test: lowest P-value=0.02 for genotype analysis, P-value=0.023 for allele analysis in all childhood ADHD; lowest P-value=0.011 for genotype analysis, P-value=0.0039 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs518147	Case-control test: lowest P-value=0.23 for genotype analysis, P-value=0.049 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs604030	Case-control test: lowest P-value=0.015 for genotype analysis, P-value=0.038 for allele analysis in all childhood ADHD; lowest P-value=0.03 for genotype analysis, P-value=0.039 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs2770296	Case-control test: lowest P-value=0.053 for genotype analysis, P-value=0.03 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs3027415	Case-control test: lowest P-value=0.0041 for genotype analysis, P-value=0.00056 for allele analysis in all adult ADHD; lowest P-value=0.031 for genotype analysis, P-value=0.011 for allele analysis in adult combined ADHD; lowest P-value=0.012 for genotype analysis, P-value=0.0055 for allele analysis in adult inattentive ADHD.	Still significant associated with adult all ADHD after corre...... Still significant associated with adult all ADHD after correcting for multiple comparisons More...	Significant
rs6561333	Case-control test: lowest P-value=0.03 for genotype analysis, P-value=0.011 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs6592961	Case-control test: lowest P-value=0.00067 for genotype analysis, P-value=0.0029 for allele analysis in all adult ADHD; lowest P-value=0.00059 for genotype analysis, P-value=0.0018 for allele analysis in adult combined ADHD. \| lowest P-value=1.90E-06 for genotype analysis, P-value=2.03E-05 for allele analysis in all childhood ADHD; lowest P-value=7.20E-05 for genotype analysis, P-value=0.00053 for allele analysis in childhood combined ADHD; lowest P-value=0.00061 for genotype analysis, P-value=0.0014 for allele analysis in childhood inattentive ADHD.	Still significant associated with all ADHD and combined ADHD...... Still significant associated with all ADHD and combined ADHD in adult and childhood groups after correcting for multiple comparisons, as well as in childhood inattentive ADHD group More...	Significant
rs6296	Case-control test: lowest P-value=0.033 for genotype analysis, P-value=0.52 for allele analysis in all childhood ADHD; lowest P-value=0.015 for genotype analysis, P-value=0.83 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs6561332	Case-control test: lowest P-value=0.04 for genotype analysis, P-value=0.0098 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs1328684	Case-control test: lowest P-value=0.014 for genotype analysis, P-value=0.19 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs1503433	Case-control test: lowest P-value=0.011 for genotype analysis, P-value=0.2 for allele analysis in adult inattentive ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs11817364	Case-control test: lowest P-value=0.046 for genotype analysis, P-value=0.024 for allele analysis in all adult ADHD; lowest P-value=0.007 for genotype analysis, P-value=0.06 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs12259062	Case-control test: lowest P-value=0.02 for genotype analysis, P-value=0.048 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs1982406	Case-control test: lowest P-value=0.022 for genotype analysis, P-value=0.1 for allele analysis in adult combined ADHD; lowest P-value=0.0044 for genotype analysis, P-value=0.0087 for allele analysis in all childhood ADHD; lowest P-value=0.00058 for genotype analysis, P-value=0.0031 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs2224721	Case-control test: lowest P-value=0.0052 for genotype analysis, P-value=0.079 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs1672717	Case-control test: lowest P-value=0.012 for genotype analysis, P-value=0.12 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs1800532	Case-control test: lowest P-value=0.015 for genotype analysis, P-value=0.03 for allele analysis in childhood combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs1150222	Case-control test: lowest P-value=0.012 for genotype analysis, P-value=0.051 for allele analysis in adult inattentive ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs1176717	Case-control test: lowest P-value=0.027 for genotype analysis, P-value=0.078 for allele analysis in adult inattentive ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant
rs11186320	Case-control test: lowest P-value=0.014 for genotype analysis, P-value=0.0049 for allele analysis in all adult ADHD; lowest P-value=0.009 for genotype analysis, P-value=0.0079 for allele analysis in adult combined ADHD.	no significance after correcting for multiple comparisons no significance after correcting for multiple comparisons	Significant

Genes reported by this study (count: 12)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
HTR3B	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
TPH1	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
HTR1D	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
DDC	Haplotype analysis: P-value=0.00053, OR=2.17 for adult ADHD;...... Haplotype analysis: P-value=0.00053, OR=2.17 for adult ADHD; P-value=0.0017, OR=1.90 for childhood ADHD. strongly associated with both adulthood and childhood ADHD. More...	Significant
HTR3A	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
HTR1F	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
MAOB	Haplotype analysis: P-value=0.0029, OR=1.90 for adult ADHD, ...... Haplotype analysis: P-value=0.0029, OR=1.90 for adult ADHD, specifically associated in the adult ADHD sample. More...	Significant
HTR6	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
HTR7	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
HTR2A	Haplotype analysis: P-value=0.0036, OR=1.63 for adults combi...... Haplotype analysis: P-value=0.0036, OR=1.63 for adults combined ADHD; P-value=0.0084, OR=1.49 for childhood combined ADHD. showed evidence of association only with the combined ADHD subtype both in adults and children. More...	Significant
HTR1B	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant
HTR2C	little evidence of association with ADHD was found. little evidence of association with ADHD was found.	Non-significant