Genetic Epidemiology Of Adhd

Evidence reviewed in the preceeding chapter suggests that ADHD is a heterogeneous condition that has many causes, and is considered as a final common pathway for a variety of complex brain developmental processes (1). The exact etiology of ADHD is unknown, but a substantial genetic element has been implicated from family, twin, and adoption studies.

2.1. Family Studies in ADHD

Family studies investigate the degree of familial clustering of a disorder. Thapar and Scourfield (2) summarize family, twin, and adoption studies in ADHD. Family studies have shown an increased risk of ADHD in the families of children with ADHD (whether defined using the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition (DSM-III) or DSM-III-R diagnostic criteria) with reported relative risks (A) of between 4 and 5.4 for first-degree relatives (3,4).

2.2. Twin Studies in ADHD

A drawback of family studies is that they cannot disentangle genetic from environmental sources of transmission. Twin and adoption studies assist in doing so. The occurrence of twinning creates a natural experiment in psychiatric genetics (5). If a disorder is strongly influenced by genetic factors then the risk to co-twins of ill probands should be greatest when the twins are monozygotic. The risk to dizygotic twins should exceed the risk to controls but

From: Attention Deficit Hyperactivity Disorder: From Genes to Patients Edited by: D. Gozal and D. L. Molfese © Humana Press Inc., Totowa, NJ

should not be greater than the risk to siblings. Twin data are used to estimate heritability (h2), which measures the degree to which a disorder is influenced by genetic factors. Twin studies (2) have consistently shown the importance of genetic influences on ADHD, whether defined as a categorical diagnosis (i.e., as defined by DSM) or as a quantitative measure of symptomatology, with reported h2 estimates of between 0.39 and 0.91.

2.3. Adoption Studies in ADHD

As with twinning, the occurrence of adoption provides another useful experiment for psychiatric genetics (5). Whereas parents can confer a disease risk to their biological children via both biological and environmental pathways, they can confer risk to adoptive children only via an environmental pathway. Thus by examining both the adoptive and the biological relatives of ill probands, genetic and environmental sources of familial transmission can be disentangled. Thapar and Scourfield (2) provide an overview of adoption studies in ADHD. Although published adoption studies of ADHD are much less recent than the twin studies and have some methodological drawbacks, such as small sample size, nonsystematic ascertainment, or the failure to use standardized measures or diagnostic criteria, overall the findings have been consistent in showing the importance of genetic factors. Biological parents of hyperactive children appear to show higher rates of hyperactivity and ADHD (4,6,7), and poorer performance on cognitive measures of attention (8) than adoptive relatives. Similarly in a study of separately fostered siblings, in accordance with expectations of a genetic etiology, hyperactive children showed greater concordance with their biological siblings than their half-siblings (9).

2.4. Mode of Genetic Transmission of ADHD

The exact mode of transmission for genes underlying ADHD remains unknown. Segregation analyses (6,10-12) have proposed models of inheritance from major gene effects through oligogenic to polygenic and multifactorial models, but the differences in statistical "fit" between multifactorial genetic models and single-gene inheritance is modest. It appears more likely that several interacting genes of modest effect cause ADHD. This multifactorial concept is consistent with ADHD's high population prevalence (2-7%) and high concordance in monozygotic twins (68-81%), but modest recurrence risks to first-degree relatives.

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