Additive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects

Halperin et al. (Halperin JM, Newcorn JH, Koda VH. Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disab ilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 19 97. 36. 1688-1696) reported a significant increase in plasma norepinephrine (NE) in attention-deficit hyperactivity disorder (ADHD) children with read ing and other cognitive disabilities compared to ADHD children without lear ning disabilities (LD). We examined the hypothesis that ADHD +/- LD was ass ociated with NE dysfunction at a molecular genetic level by testing for ass ociations and additive effects between polymorphisms at three noradrenergic genes - the adrenergic alpha 2A receptor (ADXA2A), adrenergic alpha 2C rec eptor (ADRA2C), and dopamine beta-hydroxylase (DBH) genes. A total of 336 s ubjects consisting of 274 individuals with Tourette syndrome (TS) and 62 no rmal controls were genotyped. Regression analysis showed a significant corr elation between scores for ADHD, a history of LD, and poor grade-school aca demic performance that was greatest for the additive effect of all three ge nes. Combined, these three genes accounted for 3.5% of the variance of the ADHD score (p = 0.0005). There was a significant increase in the number of variant NE genes progressing from subjects without ADI-ID (A -) or learning disorders (LD -) to A + LD - to A - LD + to A + LD + (p = 0.0017), but no comparable effect for dopamine genes. These data support an association bet ween NE genes and ADHD, especially in ADHD + LD subjects.