Replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test
Introduction : Previously we found an association between SNPs in the promoter region of DRD4 dopamine receptor & statistically-derived phenotypes generated from symptoms of attention-deficit/hyperactivity disorder (ADHD). We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. Methods : Four SNPs were genotyped in & around DRD4 in 2,631 individuals in 642 families, 1439 children (68% Ms) - 642 were siblings & 797 children with ADHD (but 674 analysed as probands) . We developed a quantitative phenotype at each SNP by weighting 9 inattentive & 9 hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. A quantitative phenotype was generated at each SNP. Then the screening procedure implemented in the PBAT (Lange 2004a & b) program for family-based association (FBAT-PC) was used to select & test the 5 SNPs / genetic model combinations with the greatest power to detect an association within each candidate gene. Results : 1/ One of the 4 SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = 0.02). 2/ A rank ordering of the correlation between each of the ADHD symptoms & the quantitative phenotype -- (a) -- suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; -- (b) -- however, it was necessary to include inattentive symptoms to achieve a significant result. . 3/ The top 3 influential variables on the phenotype were all hyperactive-impulsive variables e.g. 1) often blurts out answers before questions have been completed, 2) Is often "on the go" or often acts as if "driven by a motor", & 3) Restlessness. The most influential inattentive symptom was "Often forgetful in daily activities." . Conclusions : This study partially replicated a previous finding - [I] - by identifying an association between rs7124601 & a quantitative trait generated from ADHD symptoms. -- This SNP is located in intron 1 of DRD4 (http://snpper.chip.org/bio), 160 bp from exon 2. -- Rs7124601 is located 2.27Kb away from the initial finding & is located on the same haplotype block as the two previous SNPs, hCV26775267 & hCV26775266. Because these SNPs are within one haplotype block, possible that they identify the same genetic effect - [II] - Rs7124601 is LD with the SNPs identified previously. n.b. not the additive (462 informative families) , but the recessive model was significant (based on 330 informative families) informative = 2 genotyped people of whom one had ADHD - [III] - In contrast to the previous study, this finding suggests that both hyperactive-impulsive & inattentive symptoms are important in the association
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