Family-based association analysis of a statistically derived quantitative traits for ADHD reveal an association in DRD4 with inattentive symptoms in ADHD individuals.

The objective of this study was to determine whether single nucleotide polymorphisms (SNPs) within candidate genes for ADHD are associated with quantitative phenotypes generated from inattentive and hyperactive-impulsive symptoms. One hundred forty-three SNPs were genotyped in and around five ADHD candidate genes. A highly heritable quantitative phenotype was generated at each SNP by weighting inattentive and hyperactive-impulsive symptoms. Once these phenotypes were generated, a screening procedure was used to select and test the five SNP/phenotype combinations with the greatest power to detect an association for each candidate gene. Adjacent SNPs in the promoter region of DRD4, hCV26775267 and hCV26775266, were associated with the quantitative phenotypes generated from the ADHD symptoms (corrected P-values = 0.012 for both SNPs). The correlations between the ADHD symptoms and quantitative phenotype revealed that inattentive symptoms had a strong influence on the generated phenotype. Subsequent family-based association test-principal components (FBAT-PC) analyses using inattentive symptoms only also had significant associations. SNPs in the promoter region of DRD4 are associated with the phenotypes generated from ADHD symptoms. The strong correlation of the inattentive symptoms with these quantitative phenotypes and the subsequent FBAT-PC analyses suggest this region is primarily associated with inattentive symptoms. This analysis adds to previous findings by suggesting that variants at these loci may be specifically associated with inattentive symptoms. (c) 2007 Wiley-Liss, Inc.