Association and linkage of α-2A adrenergic receptor gene polymorphisms with childhood ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A , showed inconsistent results with regard to an Msp I polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define Hha I and Dra I restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the Msp I RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the Dra I polymorphism with the ADHD combined subtype ( P =0.03), and the quantitative TDT showed association of this polymorphism with the inattentive ( P =0.003) and hyperactive-impulsive ( P =0.015) symptom dimensions. The haplotype that contained the less common allele of the Dra I polymorphism likewise showed a strong relationship with the inattentive ( P =0.001) and hyperactive-impulsive ( P =0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the Dra I polymorphism of ADRA2A is linked to a causative polymorphism.