Is the α‐2A adrenergic receptor gene (ADRA2A) associated with attention‐deficit/hyperactivity disorder?

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex childhood-onset psychiatric disorder characterized by marked symptoms of inattention, hyperactivity, and impulsivity. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Although most of the molecular studies have investigated the dopamine D4 receptor gene (DRD4) and the dopamine transporter gene (DAT1) genes in its etiology, pharmacological and brain imaging evidences seem to indicate that genes of the adrenergic system could also be attractive for association studies. We investigated a sample of 96 Brazilian ADHD children and adolescents and their parents for the ADRA2A MspI polymorphism. Although no association with either MspI allele was observed through the haplotype relative risk (HRR) analysis, effects of the ADRA2A gene on inattention and combined (inattention + hyperactivity/impulsivity) symptom scores were detected (U = 222.5, z = 2.19, P = 0.03; and U = 208.5, z = 2.32, P = 0.02, respectively). Our results suggest that the ADRA2A gene might have a small effect on ADHD susceptibility or that this gene might modulate the severity of the disorder. They are also consistent with the noradrenergic theories of ADHD, suggesting a role for the alpha2A adrenergic receptors in the disorder.

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.…”

“…Although their HRR analysis with the disorder also yielded nonsignificant effects, this polymorphism was associated with ratings of inattention and hyperactivity, suggesting the possibility of an effect of the gene on symptom expression. 32 Both these results evaluated the G/G (alternatively denoted as m/ m) genotype as the risk genotype. Nonetheless, it is difficult to draw clear conclusions about ADHD and ADRA2A from these few preliminary studies due to conflicting findings and the fact that a sample of Tourette's syndrome patients provide the main positive findings, which may not generalize to other ADHD samples.…”

Monoamine Oxidase A Activity and Norepinephrine Level in Hippocampus Determine Hyperwheel Running in SPORTS Rats

“…The possibilities that the a 2 -ARs (Roman et al, 2003) or the NE transporters on the presynaptic membranes (Xu et al, 2000) are impaired genetically and that this results in an increase in extracellular NE level in the SPORTS rat hippocampus cannot be excluded; however, the decreased NE in the whole homogenate of SPORTS rat hippocampus prompted us to first examine the activity of MAOA, which is the enzyme catalyzing the degradation of monoamines including NE (Daniel et al, 2001). We found that the enzyme activity of MAOA, but not of MAOB, was decreased in the hippocampus of SPORTS rats.…”

Complex haplotypes derived from noncoding polymorphisms of the intronless α 2A -adrenergic gene diversify receptor expression

“…The critical roles of ␣ 2A ARs in these physiologic processes has prompted association and family studies of receptor genetic variability to identify potential risk factors or disease modifiers and pharmacogenomic studies to identify potential treatment-response loci for multiple central nervous system, cardiovascular, and metabolic diseases (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). These studies were performed with single restriction fragment-length polymorphisms (RFLPs) of the ␣ 2A AR gene, such as a DraI RFLP, and generally have shown only weak or no associations or a lack of reproducibility.…”