Years of work have affirmed that genetic factors influence the risk for anxiety disorders. One study of adults found modest heritability for GAD for both men (15%) and women (20%) and no effect of shared environment (Hettema, Prescott, & Kendler, 2001; see Table 9.3). Other research affirms the heritability of panic disorder (Crowe, 1985; Gorwood, Feingold, & Ades, 1999; Marks, 1986; Skre, Onstad, Torgersen, Lygren, & Kringlen, 1993). Merikangas and Risch (2003) suggest heritability estimates of 50% to 60% for adult panic disorder, with risk ratios ranging from 3 to 8 for first-degree relatives of adult probands with panic disorder. A meta-analysis by Hettema, Neale, and Kendler (2001) uncovered a modest genetic contribution to four anxiety categories and little or no effect of shared environment. One of the most extensive explorations of the contribution of genes to anxiety disorders is the Virginia Twin Study of Adolescent Behavioral Development (VTSABD; Eaves et al., 1997). This corpus, which relies primarily on self-report data, discovered strong additive genetic effects for OAD in both boys and girls (37%), with little effect of shared environment (Topolski et al., 1997). Silberg and colleagues (Silberg, Rutter, Neale, & Eaves, 2001) reported that 12% to 14% of the variance in OAD in girls was attributable to genes, and most of the remaining variance to nonshared environment.

The Virginia Twin Study corpus indicated a smaller genetic contribution to separation anxiety (only 4%), but large nonshared environmental effects (40% and 56%). The data for girls re vealed minimal genetic effects on separation anxiety and a greater contribution of shared environment (11% for children 8 to 12 years old, 23% for children 14 to 17 years old; Silberg, Rutter, Neale et al., 2001). However, parent-report checklists from an Australian national twin registry found a higher genetic loading for separation anxiety symptoms in girls (50%) and a much lower one for boys (14%) (Feigon, Waldman, Irwin, Levy, & Hay, 2001).

The Virginia Study indicated that about 9% to 10% of the variance in phobic symptoms was genetic in girls; the remainder was attributable to nonshared environment (Topolski et al., 1997). However, a Swedish study found that shared environmental factors explained considerably more of the variance for fears of animals, unfamiliar situations, and mutilations than non-shared environment (Lichtenstein & Annas, 2000). Thus, it is important to appreciate that conclusions based on twin studies can vary markedly as a function of the site of the laboratory, as well as the informant supplying the relevant information. When mothers reported on separation anxiety disorder in a population-based sample of female twins living in Missouri, heritability estimates were high (62%) and there was only a modest effect of shared environment.

Weissman (1988) argued almost 20 years ago that high rates of separation anxiety in children of parents who were comorbid for panic and depression disorder implied an association between separation anxiety disorder in childhood and the later development of panic disorder. There was a fairly specific association between separation anxiety in children who had been

brought to clinics and separation anxiety in the parents when they were children years earlier (Manicavasagar, Silove, Rapee, Waters, & Momartin, 2001).

In addition, there is evidence for genetic contributions to personality traits such as neuroticism and introversion (Eaves, Eysenck, & Martin, 1989), shyness (Daniels & Plomin, 1985), and behavioral inhibition (DiLalla, Kagan, & Reznick, 1994; Kagan, 1994). A group of very shy 7-year-old Israeli children were more likely than others to inherit the long form of the allele for the serotonin transporter promoter region polymorphism (Arbelle et al., 2003); however, not all studies have found this association.

Despite these findings, many studies fail to meet the highest research standards, which include the following: (1) clearly operationalized diagnostic criteria; (2) systematic ascertainment of probands and relatives; (3) direct interviews with a majority of subjects; (4) diagnostic assessment of relatives by investigators blind to the proband's status; and (5) family studies with inclusion of comparison groups (Hettema, Neale, & Kendler, 2001). These standards are occasionally met in studies with adults, but rarely in studies with children and adolescents.

Genes are only expressed within a certain envelope of environments and individuals both shape and select their environments (Rutter, Silberg, O'Connor, & Siminoff, 1999a, 1999b). Finally, it should be appreciated that the attribution of a genetic risk to an individual should not invite fatalism (Rutter et al., 1990). Some heritable conditions can be treated and a few can be controlled. The classic example is phenylketonuria, for which the cognitive impairment is caused by an inherited metabolic defect that can be controlled by restricting the child's diet.

By developing personalized treatment plans, the revolution in molecular genetics promises to transform the identification and treatment of anxiety disorders across the lifespan. Two complementary approaches are described. Pharmacogenomic studies use genomic technologies to identify chromosomal areas of interest and, hence, potential drug targets (see, for example, Arbelle et al. 2003; Smoller et al., 2003); pharmacogenetic studies identify candidate genes that moderate drug response (see, for example, Basile, Masellis, Potkin, & Kennedy, 2002), or adverse event profile (see, for example, Murphy, Kremer, Rodrigues, & Schatzberg, 2003). Identified difference may interact with age, gender, race and ethnicity (Lin, 2001).

In the adult literature on genetic factors, the most robust findings involve polymorphisms in the serotonin transporter (Weizman and Weizman, 2000). In comparison to progress in ADHD (Rohde, Roman, & Hutz, 2003), however, little is known about pharmacogenetic or pharmacogenomic approaches to anxiety disorders in the pediatric population. Shyness (Arbelle et al., 2003) and behavioral inhibition (Smoller et al., 2003) but not internalizing symptoms (Young, Smolen, Stallings, Corley, & Hewitt, 2003) all have been linked to candidate gene variation, illustrating how lack of consistency in phenotypic identification among other factors limits progress despite clear evidence from statistical genetic methods regarding the importance of genetic factors (Stein, Chavira, & Jang, 2001).

Future progress will depend on an improved understanding of the nature and identification of disease states and their natural course, which in turn will allow the development of more specific treatments, better risk prediction, and the implementation of preventive strategies based in pharmacogenomic and pharmacogenetic approaches (Gottesman and Gould, 2003; Pickar, 2003).