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	Arcos-Burgos M, 2004 (b)15094785
Citation	Arcos-Burgos M., Castellanos F. X., Konecki D., Lopera F., Pineda D., Palacio J. D., Rapoport J. L., Berg K., Bailey-Wilson J. and Muenke M. (2004) "Pedigree disequilibrium test (PDT) replicates association and linkage between DRD4 and ADHD in multigenerational and extended pedigrees from a genetic isolate." Mol Psychiatry, 9(3): 252-9.
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	14 extended and multigenerational families
Predominant Ethnicity	Paisa
Population	Colombia

Detail Info

Summary	Here, they present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120bp tandem duplication at the promoter and a 48bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.
Total Sample	14 extended and multigenerational families
Sample Collection	The blood samples were ascertained from Paisa families in Medellin, Antioquia, Colombia, South USA.
Diagnosis Description	Clinical assessments were performed with interviewers 'blind' to subjects presumptive diagnoses. Parents of school-age probands and teachers completed the DSM-IV Checklist-Antioquia version; the Strengths and Weaknesses of ADHD and Normal Behavior modified for Antioquia (SWAN-6), and the Behavioral Assessment System for Children (BASC) as translated and validated for Antioquia. Additionally, parents underwent a full-structured psychiatric interview regarding all their offspring (Diagnostic Interview for Children and Adolescents-DSM-IV version, DICA-IV, Antioquia translation). All school-age probands also underwent a full neuropsychiatric evaluation that included a full neurological examination, the Latin USAn counterpart of the Wechsler Abbreviated Scale of Intelligence, a continuous perfor-mance test, the Rey-Osterreith Complex Figure Test, the Token test, and an abbreviated Wisconsin Card Sort Test. For more detailed information, please refer to the original paper.
Technique	DRD4 genotyped polymorphisms included a 120 bp insertion/deletion polymorphism, located at the promoter region (120 bp ins/del promoter) and the 48 bp-VNTR at the exon 3 (48 bp-VNTR-exon3).
Analysis Method	Maximum LOD scores were estimated using the HOMOG suite of programs implemented in ANALYSIS. They performed a model-free non-parametric linkage (NPL) analysis based only on identity by descent (IBD) measurements at the marker loci. Owing to the large size of the pedigrees, they used SIMWALK2. The statistic computed by SIMWALK2 is the NPL-all statistic. Using the HAPLOTYPE module of SIMWALK2, they reconstructed the more probable haplotype arrangements for these two loci to perform family-based association studies involving haplotypes. This haplotype analysis estimates the most likely of fully typed maternal and paternal haplotypes of the marker loci for each individual belonging to a particular pedigree. They also used the pedigree disequilibrium test (PDT), a recently described FBAT, which incorporates information from all members of the pedigree with genotypic and phenotypic data retaining the properties of the original TDT; in particular, it is valid as a test of both linkage and association even when there is population stratification. They estimated the power of this set of families using PBAT. They applied the PDT to each marker and to the haplotype configurations as reconstructed after using SIMWALK2. The gene frequencies for the alleles at the marker loci were estimated using DOWNFREQ as adapted to ANALYSIS and based on the founder individuals' genotypes. Linkage disequilibrium analyses were performed with ARLEQUIN.
Result Description	Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD.

Other variant reported by this study (count: 2)

Variant Name	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
DRD4 exon3 VNTR	7 repeat		two-point LOD=-3.18 under model I, two-point LOD=-4.74 under...... two-point LOD=-3.18 under model I, two-point LOD=-4.74 under model II, two-point LOD=-3.21 under model III, NPL P-value=0.4194, PDT smallest P-value=0.0578 for 7R More...	Two-point LOD scores were significantly negative; Non-parametrical analysis resulted in nonsignificant evidence for linkage	Non-significant
DRD4 promoter duplication 120bp			two-point LOD=-3.89 under model I, two-point LOD=-7.66 under...... two-point LOD=-3.89 under model I, two-point LOD=-7.66 under model II, two-point LOD=-3.7 under model III, NPL P-value=0.4231, PDT P-value=0.5835 More...	Two-point LOD scores were significantly negative; Non-parametrical analysis resulted in nonsignificant evidence for linkage	Non-significant

Genes reported by this study (count: 1)