Ten years after Hechtman's review (76), studies are only starting to get under way to test her argument that genetic influences on NE will inform on ADHD. Genetic studies of features important to NE transmission and relevant to the ADHD condition have been few. They have concentrated on the a-2a site for which NE has high affinity (where increased binding has been related to stress and frontal lobe cognition [77,78]) and the reuptake site, which if blocked (like the a-2a site) will lead to a decrease of neuronal firing (79). Metabolic enzymes (DBH, Catechol-0-methyl transferase [COMT], and MAO; Fig. 1) have also received some attention. MAO activity, relevant for the breakdown of all the monoamines, has been inversely related to the expression of personality features thought to be relevant for groups or subgroups of ADHD subjects (e.g., impulsiveness, aggression, and sensation-seeking; see discussion in 80).
*This difference may be further exaggerated by a leftward bias in males compared to a rightward bias of D1 binding in females. However, with maturation there is a decrease in the asymmetry in terms of DA and its metabolism (75).
A study using a so-called "line-item" approach to the a-2a receptor (approximately the inverse of more conventional studies with single base-pair polymorphisms) found an allele associated with clusters of symptoms relevant to ADHD along with oppositional and conduct disorders (81). In contrast to this, another allele the study examined related to anxiety and schizoid features. Studies focusing on this receptor seem promising. In contrast to the situation with DA, first reports on several polymorphisms relating to the NE transporter (NET1) have drawn a blank (82,83). There is no evidence as yet that the NET is relevant to the heri-tability of the ADHD phenotype.
COMT activity is relevant to both DA and NE metabolism (Fig. 1). There is a low activity allele with methionine substitutions that is reported to be preferentialy transferred in male Han Chinese with ADHD, whereas the high-activity form with valine substitutions was more common in the females (84). Although there is support for the transmission of the valine form in Israeli triads (85), in view of negative results from three other countries, the situation remains controversial.
Several polymorphisms have figured in studies of the genetic transmission of DBH (also for TOH), but there is little evidence for preferential transmission in ADHD (see ref. 86) and none for linkage (87). Consideration of MAO heritability also seems irrelevant to questions concerning the roles of NE and 5-HT in ADHD. Associations were reported from a case-control study of ADHD with comorbid externalizing problems (88) but earlier reports of relationships to novelty-seeking have not been replicated (89).
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