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	Ribases M, 2009(a)19733838
Citation	Ribases M., Bosch R., Hervas A., Ramos-Quiroga J. A., Sanchez-Mora C., Bielsa A., Gastaminza X., Guijarro-Domingo S., Nogueira M., Gomez-Barros N., Kreiker S., Gross-Lesch S., Jacob C. P., Lesch K. P., Reif A., Johansson S., Plessen K. J., Knappskog P. M., Haavik J., Estivill X., Casas M., Bayes M. and Cormand B. (2009) "Case-control study of six genes asymmetrically expressed in the two cerebral hemispheres: association of BAIAP2 with attention-deficit/hyperactivity disorder." Biol Psychiatry, 66(10): 926-34.
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	587 (270 adults and 317 children) patients and 531 controls from Spanish population
Predominant Ethnicity	Caucasian
Population	Spain, Germany, Norway
Gender	Spanish population: 78% were males; German population: 50% were males; Norwegian population: 52% were males.
Age Group	Children/Adolescents and Adults : Spanish population: mean age 30.2 years (SD=12.1) for adult patients, 9.3 years (SD=2.6) for child patients, 39.9 years (SD=17.0) for control subjects; German population: mean age 34.3 years (SD=10.4) for patients and 31.2 years (SD=10.3) for control subjects; Norwegian population: mean age 35.4 years (SD=11.5) for patients.

Detail Info

Summary	They selected six functional candidate genes showing at least 1.9-fold differential expression between hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6, ATP2B3, and ID2) and performed a case-control association study in an initial Spanish sample of 587 ADHD patients (270 adults and 317 children) and 587 control subjects. Results: The single- and multiple-marker analysis provided evidence for a contribution of BAIAP2 to adulthood ADHD. They thus tested BAIAP2 for replication in two independent adult samples from Germany (639 ADHD patients and 612 control subjects) and Norway (417 ADHD cases and 469 control subjects).While no significant results were observed in the Norwegian sample, they replicated the initial association between BAIAP2 and adulthood ADHD in the German population. Their results support the participation of BAIAP2 in the continuity of ADHD across life span, at least in some of the populations analyzed, and suggest that genetic factors potentially influencing abnormal cerebral lateralization may be involved in this disorder.
Total Sample	A total of 1643 ADHD Caucasoid patients were included in this study: 587 (270 adults and 317 children) from Spain, 639 from Germany, 417 from Norway. A total of 1612 cases were included: 531 from Spain, 612 from Germany, 469 from Norway.
Replication Size	639 cases and 612 controls from German population; 417 cases and 469 controls from Norwegian population
Sample Collection	All ADHD patients (from Spain, Germany and Norway) are Caucasoid
Diagnosis Description	Diagnosis was blind to genotype. For detailed information of clinical assessment and diagnostic instruments in four populations (Spanish adult ADHD, Spanish childhood ADHD, German and Norwegian population), please refer to the original paper.
Technique	DNA samples were isolated either from saliva using the Oragene DNA Self-Collection Kit (DNA Genotek, Kanata, Ontario, Canada) or from blood by the salting-out procedure or using magnetic bead technology with the Chemagic Magnetic Separation Module I and the Chemagic DNA Kit (Chemagen, Baesweiler, Germany). DNA concentrations were determined using the PicoGreen dsDNA Quantitation Kit (Molecular Probes, Eugene, Oregon). Six functional candidate genes showing at least 1.9-fold differential expression between hemispheres (BAIAP2, DAPPER1, LMO4, NEUROD6, ATP2B3, and ID2) were selected. Thirty-one tagSNPs were chosen with these criteria. An additional nonsynonymous SNP, rs17832998, located within exon 4 of DAPPER1, was included in the analysis. To detect population admixture, 48 unlinked anonymous SNPs located at least 100 kb distant from known genes were also genotyped. In Spanish and German populations, the 32 selected SNPs were assessed with an automated assay design pipeline; all SNPs were genotyped using the SNPlex platform; two HapMap samples (NA11992 and NA11993) were included in all assays and a concordance rate of 100% was obtained. In Norwegian population, genotyping was carried out by the multiplex MassARRAY iPLEX System (SEQUENOM, San Diego, California).
Analysis Method	They performed a two-stage association study. They first carried out a case-control association analysis in a Spanish sample that included adult and child ADHD patients and control subjects. Genes showing positive signals were then tested for replication in two independent case-control samples from Germany and Norway. 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 0.16. They tested genetic stratification in the Spanish and German samples by analyzing the SNPs in Hardy-Weinberg equilibrium (HWE) from the 48 anonymous SNPs set with two different approaches: 1) the F-statistics (Fst) coefficient calculated by the Weir and Cockerham approach with the FSTAT software; and 2) the method of Pritchard and Rosenberg. For detailed information of single-marker analysis and multiple-marker analysis, please refer to the original publication.
Result Description	The single-marker analysis identified two SNPs in BAIAP2 displaying nominal association with ADHD in the adult dataset: rs8079781 and rs4969385 ; differences that did not remain statistically significant after Bonferroni correction. No association, however, was observed in the childhood ADHD sample. For the haplotype-based analysis of BAIAP2 only in the adult dataset, the study of the 13 BAIAP2 SNPs revealed a four-marker haplotype (rs8079626/rs11657991/rs7503597/rs7210438) associated with adult ADHD. The analysis of the contribution of individual haplotypes to the phenotype showed overrepresentation of the A-G-G-C allelic combination and a trend toward underrepresentation of the A-C-G-C haplotype in the adult sample. The frequency of the A-G-G-C risk haplotype carriers confirmed the association between BAIAP2 and adult ADHD . Interestingly, these differences were specific to the combined ADHD subgroup with overrepresentation of the same risk haplotype and an increased frequency of carriers of this allelic combination in this clinical dataset. No evidence of association between BAIAP2 and the inattentive clinical subset was observed. All the associations from haplotype-based analysis above remained significant once adjusted for multiplicity. The 13 SNPs within the BAIAP2 gene were selected for follow-up in replication adult cohorts from Germany and Norway. The single-marker analysis detected a nominal association between rs8079626 and ADHD. The multiple-marker approach showed evidence of association between adult ADHD and a two-marker haplotype (rs8079626/rs7210438 . Consistently with the results in the Spanish cohort, an overrepresentation of the A-C allelic combination was observed in the German ADHD sample, whereas the G-C haplotype was downrepresented. As in the Spanish series, once patients were subdivided according to the ADHD subtypes, the association between BAIAP2 and adult ADHD remained significant only in the combined ADHD sample. No evidence of association between adult ADHD and the BAIAP2 gene was detected in the Norwegian cohort in the analysis of single or multiple markers.

SNPs reported by this study (count: 13)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs4969385			Case-control test: P-value=0.02 for genotype analysis, P-value=0.01 for allele analysis in Spanish adult ADHD group; P-value=0.99 for genotype analysis, P-value=0.89 for allele analysis in Spanish childhood ADHD group; P-value=0.24 for genotype analysis, P-value=0.66 for allele analysis in German adult ADHD group; P-value=0.81 for genotype analysis, P-value=0.60 for allele analysis in Norwegian adult ADHD group.	significant association with adult ADHD was found in Spanish...... significant association with adult ADHD was found in Spanish population More...	Significant
rs6565531			Case-control test: P-value=0.61 for genotype analysis, P-value=0.85 for allele analysis in Spanish adult ADHD group; P-value=0.90 for genotype analysis, P-value=0.65 for allele analysis in Spanish childhood ADHD group; P-value=0.18 for genotype analysis, P-value=0.06 for allele analysis in German adult ADHD group.	No association was found. No association was found.	Non-significant
rs4969245			Case-control test: P-value=0.67 for genotype analysis, P-value=0.72 for allele analysis in Spanish adult ADHD group; P-value=0.31 for genotype analysis, P-value=0.45 for allele analysis in Spanish childhood ADHD group; P-value=0.92 for genotype analysis, P-value=0.82 for allele analysis in German adult ADHD group; P-value=1.00 for genotype analysis, P-value=0.98 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant
rs4969349			Case-control test: P-value=0.26 for genotype analysis, P-value=0.89 for allele analysis in Spanish adult ADHD group; P-value=0.69 for genotype analysis, P-value=0.58 for allele analysis in Spanish childhood ADHD group; P-value=0.51 for genotype analysis, P-value=0.46 for allele analysis in German adult ADHD group; P-value=0.75 for genotype analysis, P-value=0.53 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant
rs4075482			Case-control test: P-value=0.29 for genotype analysis, P-value=0.17 for allele analysis in Spanish adult ADHD group; P-value=0.13 for genotype analysis, P-value=0.05 for allele analysis in Spanish childhood ADHD group.	No association was found. No association was found.	Non-significant
rs4076037			Case-control test: P-value=0.64 for genotype analysis, P-value=0.33 for allele analysis in Spanish adult ADHD group; P-value=0.06 for genotype analysis, P-value=0.48 for allele analysis in Spanish childhood ADHD group; P-value=0.29 for genotype analysis, P-value=0.81 for allele analysis in German adult ADHD group; P-value=0.46 for genotype analysis, P-value=0.33 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant
rs11657991			Case-control test: P-value=0.31 for genotype analysis, P-value=0.13 for allele analysis in Spanish adult ADHD group; P-value=0.26 for genotype analysis, P-value=0.90 for allele analysis in Spanish childhood ADHD group; P-value=0.70 for genotype analysis, P-value=0.43 for allele analysis in German adult ADHD group; P-value=0.60 for genotype analysis, P-value=0.46 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant
rs11659017			Case-control test: P-value=0.82 for genotype analysis, P-value=0.52 for allele analysis in Spanish adult ADHD group; P-value=0.83 for genotype analysis, P-value=0.85 for allele analysis in Spanish childhood ADHD group; P-value=0.58 for genotype analysis, P-value=0.31 for allele analysis in German adult ADHD group; P-value=0.59 for genotype analysis, P-value=1.00 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant
rs8079781			Case-control test: P-value=0.01 for genotype analysis, P-value=0.01 for allele analysis in Spanish adult ADHD group; P-value=0.97 for genotype analysis, P-value=0.82 for allele analysis in Spanish childhood ADHD group; P-value=0.19 for genotype analysis, P-value=0.24 for allele analysis in German adult ADHD group; P-value=0.74 for genotype analysis, P-value=0.61 for allele analysis in Norwegian adult ADHD group.	significant associations with adult ADHD were found both in ...... significant associations with adult ADHD were found both in Spanish and German population More...	Significant
rs8067235			Case-control test: P-value=0.75 for genotype analysis, P-value=0.43 for allele analysis in Spanish adult ADHD group; P-value=0.95 for genotype analysis, P-value=0.95 for allele analysis in Spanish childhood ADHD group; P-value=0.89 for genotype analysis, P-value=0.72 for allele analysis in German adult ADHD group; P-value=0.73 for genotype analysis, P-value=0.59 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant
rs8079626			Case-control test: P-value=0.33 for genotype analysis, P-value=0.30 for allele analysis in Spanish adult ADHD group; P-value=0.54 for genotype analysis, P-value=0.44 for allele analysis in Spanish childhood ADHD group; P-value=0.05 for genotype analysis, P-value=0.04 for allele analysis in German adult ADHD group; P-value=0.82 for genotype analysis, P-value=0.58 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Significant
rs7210438			Case-control test: P-value=0.62 for genotype analysis, P-value=0.83 for allele analysis in Spanish adult ADHD group; P-value=0.87 for genotype analysis, P-value=0.64 for allele analysis in Spanish childhood ADHD group; P-value=0.52 for genotype analysis, P-value=0.42 for allele analysis in German adult ADHD group; P-value=0.26 for genotype analysis, P-value=0.39 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant
rs7503597			Case-control test: P-value=0.79 for genotype analysis, P-value=0.50 for allele analysis in Spanish adult ADHD group; P-value=0.52 for genotype analysis, P-value=0.25 for allele analysis in Spanish childhood ADHD group; P-value=0.71 for genotype analysis, P-value=0.40 for allele analysis in German adult ADHD group; P-value=0.27 for genotype analysis, P-value=0.32 for allele analysis in Norwegian adult ADHD group.	No association was found. No association was found.	Non-significant

Genes reported by this study (count: 6)

Gene	Statistical Values/Author Comments	Result of Statistical Analysis
NEUROD6	No available data. No significant association with ADHD was ...... No available data. No significant association with ADHD was found. More...	Non-significant
ATP2B3	No available data. No significant association with ADHD was ...... No available data. No significant association with ADHD was found. More...	Non-significant
BAIAP2	P-value=0.0026 for single-marker analysis, P-value=0.0016 fo...... P-value=0.0026 for single-marker analysis, P-value=0.0016 for multiple-marker analysis in spanish population; P-value=0.0062 in German population. Significant association between BAIAP2 and adulthood ADHD was observed. More...	Significant
DACT1	No available data. No significant association with ADHD was ...... No available data. No significant association with ADHD was found. More...	Non-significant
ID2	No available data. No significant association with ADHD was ...... No available data. No significant association with ADHD was found. More...	Non-significant
LMO4	No available data. No significant association with ADHD was ...... No available data. No significant association with ADHD was found. More...	Non-significant