Review
Childhood and Adolescent Anxiety and Depression: Beyond Heritability

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Objective

To review the methodology of behavior genetics studies addressing research questions that go beyond simple heritability estimation and illustrate these using representative research on childhood and adolescent anxiety and depression.

Method

The classic twin design and its extensions may be used to examine age and gender differences in the genetic determinants of complex traits and disorders, the role of genetic factors in explaining comorbidity, the interaction of genes and the environment, and the effect of social interaction among family members. An overview of the methods typically employed to address such questions is illustrated by a review of 34 recent studies on childhood anxiety and depression.

Results

The review provides relatively consistent evidence for small to negligible sex differences in the genetic etiology of childhood anxiety and depression, a substantial role of genetic factors in accounting for the temporal stability of these disorders, a partly genetic basis of the comorbidity between anxiety and depression, a possible role of the interaction between genotype and the environment in affecting liability to these disorders, a role of genotype-environment correlation, and a minor, if any, etiological role of sibling interaction.

Conclusion

The results clearly demonstrate a role for genetic factors in the etiology and temporal stability of individual differences in childhood anxiety and depression. Clinical implications of the findings are discussed.

Section snippets

Classic Twin Design and Heritability Estimation

The classical twin design is used to decompose phenotypic variance (the statistical term to quantify variation or individual differences) in one or more traits into components due to additive genetic (A), shared environmental (C), and unique environmental (E) factors. We assume that the additive genetic variance is attributable to the contribution of an unspecified number of genes, and the environmental variance to the contribution of an unspecified number of environmental events. In humans,

Beyond Heritability

Using the classical twin design, researchers have established the role of genetic and environmental factors in virtually all psychiatric traits. Currently, due to several developments that took place over the last half of the past century, it is possible to move beyond the basic question of heritability. These developments include the large-scale collection of phenotypic data by well-validated standardized questionnaires, and the collection of extensive genotypic (i.e., DNA) and environmental

Sex Differences in the Genetic Architecture of Anxiety and Depression

Does the heritability of a disorder differ between the sexes? Are the genetic effects in males and females attributable to the same genes, whose affects are possibly modulated by sex, or to different genes? The former suggests a quantitative sex difference in the genetic architecture; the latter, a qualitative difference. These questions, which may also be posed with respect to environmental effects, may be addressed within the framework of the twin design.

Quantitative and qualitative sex

Age Differences in the Genetic Architecture of Anxiety and Depression

Genetic and environmental effects may be age-dependent. For instance, there is no reason to assume that environmental or genetic influences on anxiety or depression at age 5 years are identical to those at age 10 years. To establish such differences one can study twins who differ with respect to age. However, the correct interpretation of any established difference requires a study of twins in a longitudinal design, in which phenotypes are measured in the same twins at two or more occasions.

Comorbidity

Twin design may be employed to address the question of whether the co-occurrence of two disorders has a genetic basis, an environmental basis, or results from a direct causal interaction between the disorders (e.g., depression directly causing anxiety). To address the question of comorbidity, the correlation between members of MZ and DZ twin pairs on different measures (e.g., depression in twin 1 and anxiety in twin 2) is calculated. A higher MZ correlation than DZ correlation is taken to

Genotype-Environment Interaction

Although genetic and environmental effects on childhood anxiety and depression have been well-established within the genetic epidemiologic literature, most studies have not examined how these factors combine in affecting liability to illness. It is frequently assumed, implicitly or explicitly, that genes and the environment affect the phenotype independently of each other. This is not necessarily the case.

For instance, assume an environmental factor, say an important life event, and a single

Genotype-Environment Correlation

In the traditional twin design, the genetic and environmental contributions to individual differences are usually assumed to be independent or uncorrelated. However, the possibility of genotype-environment correlation (rGE) is widely recognized. In fact, three types of rGE are distinguished, namely passive, evocative, and active. Passive rGE refers to the case in which children inherit genes and an environment that predispose them to a given phenotypic outcome.48 For an example of this, think

Social Interaction Among Family Members

The MZ and DZ twins, like other siblings, continually interact as they grow up together. In this process the behavior of one sibling may influence the behavior of the other. If variance in the behavior of interest is in part genetic, then this implies that by their interaction, the genotypic factors of one sibling (i.e., his or her specific genotype) exert an influence on the phenotypic behavior of the other sibling.53

Such sibling interaction effects may be cooperative or competitive, depending

Discussion

Our review demonstrates the role of genetic factors in the etiology of depression and anxiety in the normal distribution. In so far as one subscribes to a dimensional model of psychopathology59 in which affected children are considered to occupy the extreme of the population distribution, these results are strongly relevant. The implication of genetic factors per se clearly does not mean that the child's level of anxiety or depression is immutable, or that environmental interventions are

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    This article is discussed in an editorial by Drs. James J. Hudziak and Stephen V. Faraone on page 729.

    This research was supported by the Database Twin Register (NWO 575-25-006 and 904-57-94), Spinozapremie (NWO/SPI 56-464-14192), and the Twin-Family Database for Behavior Genetics and Genomics Studies (NWO grant 480-04-004).

    This is one of several articles published in the August and September issues of the Journal of the American Academy of Child and Adolescent Psychiatry that explores the intersection of genetics and mental health disorders in children and adolescents. The editors invite the reader to investigate the additional articles on this burgeoning area of developmental psychopathology.

    Disclosure: Dr. Middeldorp receives financial support from the Netherlands Organization for Scientific Research (NWO), the Center for Medical Systems Biology: Multifactorial Diseases: Common Determinants, Unifying Technologies (NWO Genomics) and Neuroscience Campus Amsterdam, and the EMGO Institute for Health and Care Research. Ms. Franić receives financial support from the Netherlands Organization for International Cooperation in Higher Education (Nuffic [HSP Huygens programma]). Drs. Dolan and Boomsma and Ms. Ligthart report no biomedical financial interests or potential conflicts of interest.

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