poorly on standardized measures of attention than do adop- tive relatives of children with ADHD (107).
Segregation Analysis Studies
Segregation analysis provides evidence of genetic transmis- sion by demonstrating that the pattern of illness in families is consistent with known genetic mechanisms. An early ap- proach to this was reported by Morrison and Stewart, who concluded that polygenic inheritance was a likely mode of transmission for ADHD (108). Contrasting data were pre- sented by Deutsch et al. (109). They found preliminary evidence for a single dominant gene regulating the transmis- sion of ADHD and minor physical anomalies in 48 families. Similarly, Faraone et al. reported that the familial distribu- tion of ADHD was consistent with the effects of a single major gene (75). Similar results were since reported in a twin study by Eaves et al. (110) and in a pedigree study by Hess et al. (111). Consistent findings also emerged from South America (112). Based on a sample of families from Colombia, the only models of inheritance that could not be rejected were those of dominant and codominant major gene effects. Finally, when families of ADHD probands were ascertained by the father’s diagnosis of substance abuse, Maher et al. found that a sex-dependent mendelian codomi- nant model was the best explanation for the pattern of trans- mission of ADHD (113).
Although the segregation analyses of ADHD suggest that a single gene of major effect is involved in the origin of ADHD, the differences in fit among genetic models was modest. This was especially true for the comparison of mul- tifactorial and single gene inheritance. Several interpreta- tions of these results are possible. If ADHD had more than one genetic cause, then the evidence of any single mode of transmission could be relatively weak. Alternatively, ADHD may be caused by several interacting genes of modest effect. This latter idea is consistent with ADHD’s high population prevalence (2% to 7% for ADHD) and high concordance in monozygotic twins but modest recurrence risks in first- degree relatives.
The studies by Deutsch et al. and Faraone et al. predicted that only about 40% of children carrying the putative ADHD gene would develop ADHD. This finding and other features of the genetic epidemiology of ADHD suggest that such a gene likely interacts with other genes and environ- mental factors to produce ADHD. Moreover, the segrega- tion studies indicated that about 2% of people without the ADHD gene would develop ADHD, a finding suggesting that nongenetic forms of ADHD may exist.
Chromosomal Anomalies and Molecular Genetic Studies
Anomalies in the number or gross structure of chromosomes usually lead to very early-onset disorders having severe clini-
Chapter 43: Pathophysiology of ADHD
cal manifestations (e.g., mental retardation, gross physical anomalies). No systematic studies of gross chromosomal anomalies in ADHD have been conducted, but there are several reports that such anomalies cause hyperactivity and inattention. Examples include the fragile X syndrome, du- plication of the Y chromosome in boys, and loss of an X chromosome in girls. These associations are intriguing but rare. Thus, they can account for only a very small proportion of cases of ADHD.
Molecular genetic studies use the methods of linkage and association to search for aberrant genes that cause disease. Such studies of ADHD are relatively new and far from definitive. Hauser et al. demonstrated that a rare familial form of ADHD is associated with generalized resistance to thyroid hormone, a disease caused by mutations in the thy- roid receptor- gene (114). The thyroid receptor- gene cannot, however, account for many cases of ADHD because the prevalence of generalized resistance to thyroid hormone is very low among patients with ADHD (1 in 2,500) (115), and, among pedigrees with generalized resistance to thyroid hormone, the association between ADHD and the thyroid receptor- gene has not been consistently found (116).
Several research teams have examined candidate genes in dopamine pathways because, as discussed earlier, animal models, theoretic considerations, and the effectiveness of stimulant treatment implicate dopaminergic dysfunction in the pathophysiology of this disorder. Several groups have reported an association between ADHD and dopamine D4 receptor gene (DRD4) gene (117–123). Notably, each study showed the 7-repeat allele of DRD4 to be associated with ADHD despite the use of different diagnostic systems (DSM-IIIR and DSM-IV) and measures of ADHD (rating scales and structured interviews). However, like many find- ings in psychiatric genetics (91), these positive findings are offset by some negative studies (124–128).
The positive DRD4 findings could be caused by another gene in linkage disequilibrium with DRD4 or another var- iant within DRD4. However, because the DRD4 7-repeat allele mediates a blunted response to dopamine, it is a bio- logically reasonable risk factor for ADHD (129). The 7- repeat allele has also been implicated in novelty seeking, a personality trait related to ADHD (130,131). Moreover, both norepinephrine and dopamine are potent agonists of DRD4 (132).
When the D4 gene is disabled in a knockout mouse model, dopamine synthesis increases in the dorsal striatum, and the mice show locomotor supersensitivity to ethanol, cocaine, and methamphetamine. (133). D4 knockout mice also show reduced novelty-related exploration (134), a find- ing consistent with human data suggesting a role for D4 in novelty-seeking behaviors.
Cook et al. reported an association between ADHD and the 480-bp allele of the DAT gene using a family-based association study (135). This finding was replicated by Gill et al. (136), Daly et al. (126), and Waldman et al. (137), but