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

Abstract

Halperin et al. (Halperin JM. Newcorn JH, Koda VH, Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688 1696) reported a significant increase in plasma norepinephrine (NE) in attention-deficit hyperactivity disorder (ADHD) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). We examined the hypothesis that ADHD + LD was associated with NE dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at three noradrenergic genes the adrenergic alpha2A receptor (ADRA2A), adrenergic alpha2C receptor (ADRA2C), and dopamine beta-hydroxylase (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of LD, and poor grade-school academic performance that was greatest for the additive effect of all three genes. 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 ADHD (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 between NE genes and ADHD, especially in ADHD + LD subjects.

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

“…Previous studies implicated the m allele (the rarer G allele) of the MspI marker in the risk for ADHD. 29,30,32,46 We found a trend for association and linkage between the m allele of MspI and ADHD using the TDT (P ¼ 0.13 for ADHD-C and P ¼ 0.086 for ADHD-C þ PI). In contrast, TDT analysis of the DraI RFLP yielded clearly significant results for ADHD-C (P ¼ 0.03) but not for ADHD-PI (P ¼ 0.37), as well as for both subtypes combined (ie, P ¼ 0.028 for ADHD-C þ PI).…”

“…11 Despite its potential relevance, only a handful of studies have investigated the ADRA2A gene as a potential risk factor for the development of ADHD. [29][30][31][32]46 Those studies analyzed an MspI polymorphism in the promoter of the gene and looked for association with ADHD and/or its symptoms using a variety of statistical approaches. Comings et al found that in Tourette's syndrome patients who also met DSM-IV criteria for ADHD, there was a modest correlation between symptom scores and the MspI polymorphism, but the degree to which that sample represented the complete spectrum of ADHD patients is unclear.…”

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

“…While factors involved in cell cycle regulation and cell maturation, as well as protein tyrosine kinases, are notably altered in expression between the three study groups in analysis of GO, by far the most significant finding for this region is an apparent dysregulation of adenosine 5 0 -triphosphate (ATP) production in the tricarboxylic acid (TCA) cycle, and associated change in expression of enzymes with ATPase activity coupled to transport of ions across the cell membrane. The a-2a adrenoreceptor (ADRA2A), a G-protein-coupled receptor that has been associated with severity of attention deficit hyperactivity disorder, 16 and protocadherin 9 (PCDH9), a calcium-dependent cell adhesion molecule, were both reduced significantly in the depressed suicides compared with controls. In contrast, synapsin II (SYN2) was seen to be elevated in depressed suicides over controls.…”

Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder

“…Kopeckova et al investigated a polymorphism in the promoter region of the gene encoding DA beta-hydroxylase, an enzyme that reduces NE synthesis, and found that the affected children had poor sustained attention, weaker impulse control, and impaired executive function [71] . Genetic alterations in α 2A -adrenoceptors also impair PFC executive function, and lead to conditions seen in ADHD [72] . Thus, prefrontal α [38] and Biol Psychiatry, 2005 [39] ).…”

“…The results showed that yohimbine infused into the medial PFC dose-dependently induced hyperactivity in rats of different ages, and the trends showed that the younger the rats, the more hyperactivity reduces NE synthesis, and found that the affected children had poor sustained attention, weaker impulse control, and impaired executive function [71] . Genetic alterations in α 2A -adrenoceptors also impair PFC executive function, and lead to conditions seen in ADHD [72] . Thus, prefrontal α 2A -adrenoceptors are required for attention and behaviors in humans too.…”