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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.

Chapter 3. Genetics and Genomics


Genetics and genomics have become among the most important tools in modern psychiatric research. Spurred by the completion of the human genome sequence in February 2001, the number of psychiatric genetic studies has increased dramatically in the past two decades (Lander et al. 2001; Venter et al. 2001). The following chapter will attempt to cover the basic methodologies and concepts, and define key terms, currently used in psychiatric genetics and genomics. Our goal is to facilitate interpretation by working physicians and scientists in the field of psychopharmacology of the avalanche of genetic and genomic data that are accumulating in the human neuroscience literature. Throughout this chapter, terms in common use in the genetics and genomics literature will be italicized upon their first use and definition.


Genetic epidemiological studies have established that most psychiatric disorders, as well as many nonpathological human behavioral traits, have a substantial genetic component. Investigations in genetic epidemiology therefore provide the scientific foundation for molecular genetic and genomic studies of human behavior and behavioral disorders (Kendler 1993, 2001; Plomin and Kosslyn 2001). Genetic epidemiology uses family, twin, and adoption studies to assess the contribution of familial, environmental, and genetic factors to a trait of interest. Family studies can establish that a given disorder "runs in families" but cannot easily distinguish whether such familiality is due to genetic or environmental factors. An everyday example of the distinction between genetic and familial (but environmental) traits is the difference between the ability to acquire language (a genetic trait that distinguishes humans from other species) and the native language spoken by a given person, which is familial, but entirely environmentally determined.

Adoption and twin studies distinguish between genetic and environmental influences on traits by accounting for each separately. Adoption studies investigate whether an individual's risk for a psychiatric disease depends on the mental health status of the biological or adoptive parents to disentangle genetic (i.e., similarity to biological parents, who have had little or no interaction with the adoptee) from environmental (i.e., similarity to adoptive parents, who have provided the adoptee with his or her family/social environment) influence (Cadoret 1986; Tienari and Wynne 1994; Tienari et al. 2004). Practical, ethical, and legal obstacles make large-scale adoption studies very difficult to conduct. Twin studies, while also quite challenging, are more tractable, and large twin registries are now available across the world (Busjahn 2002). These studies have provided the bulk of strong evidence supporting genetic contributions to psychiatric disorders and human behavioral traits.

In twin studies one determines what the probability of one twin being affected with a given trait or disorder, given the affectation status of the co-twin. This degree of correlation between twins for the investigated trait is then compared between monozygotic (MZ) and dizygotic (DZ) twins to gain information on the degree of genetic and environmental influence on a certain trait. MZ twins result from a separation of the zygote to yield two genetically identical embryos. DZ twins result from the separate fertilization of two eggs in the same pregnancy. DZ twins thus only share on average 50% of their genes, similar to siblings born in separate pregnancies. While neither the pre- or postnatal environments of twins are perfectly identical, to a first approximation MZ and DZ twins are equally correlated for relevant environmental exposures (Kendler and Gardner 1998). The trait correlation between MZ and DZ twins therefore allows estimation of the degree to which additive genetic, shared, or individual-specific environment contributes to the likelihood of a given trait. Figure 3-1 summarizes relative contributions of each factor, estimated from patterns of correlation between MZ and DZ twins (for a methodological review of this topic, see Bulik et al. 2000).

FIGURE 3-1. Patterns of intrapair correlations and source of variance implied.

FIGURE 3-1. Patterns of intrapair correlations and source of variance implied.

Intrapair correlations around zero imply effects of individual-specific environment. Equal intrapair correlations greater than zero that are equal for monozygotic (MZ) and dizygotic (DZ) twins imply effects of shared environment. Correlations for MZ twins that are twice as great as those for DZ twins imply additive genetic effects. Correlations for MZ twins that are greater than—but not twice as great as—those for DZ twins imply additive genetic effects and shared environment effects. The correlations of less than 1.0 in the last three examples are likely mediated by individual-specific environment effects.

Intrapair correlations around zero imply effects of individual-specific environment. Equal intrapair correlations greater than zero that are equal for monozygotic (MZ) and dizygotic (DZ) twins imply effects of shared environment. Correlations for MZ twins that are twice as great as those for DZ twins imply additive genetic effects. Correlations for MZ twins that are greater than—but not twice as great as—those for DZ twins imply additive genetic effects and shared environment effects. The correlations of less than 1.0 in the last three examples are likely mediated by individual-specific environment effects.

Twin studies have firmly established important genetic contributions for all psychiatric disorders, with heritability estimates (i.e., the proportion of risk for a disorder attributable to the additive effects of genes) ranging from 30% from 80% for most common psychiatric disorders (see Table 3-1). Interestingly, the importance of shared environment seems to be of significant relevance mostly in schizophrenia, whereas in most other disorders, including anxiety and mood disorders, individual-specific but not shared environment is the major environmental contributor to susceptibility.

TABLE 3-1. Heritability scores for major psychiatric illnesses, with focus on results of recent meta-analyses

Disorder Heritability

Autism >0.8

Schizophrenia 0.81 (0.73-0.9)

Bipolar disorder 0.79-0.85

Major depression 0.37 (0.31-0.42)

Panic disorder 0.43 (0.32-0.53)

Generalized anxiety disorder 0.32 (0.24-0.39)

Specific phobias 0.25-0.35

Social phobias 0.20-0.30

Agoraphobia 0.37-0.39

Obsessive-compulsive disorder 0.45-0.65 (children) 0.27-0.47 (adults)

N in meta-analysis References

Bailey et al. 1995; Rutter 2000 12 studies (Sweden, US, England, Norway, Denmark, Finland, Germany) Sullivan et al. 2003 (meta-analysis)

Kendler et al. 1995b; McGuffin et al. 2003 5 studies (UK, Sweden, US), N >21,000 Sullivan et al. 2000 (meta-analysis)

3 studies, N >9,000 Hettema et al. 2001 (meta-analysis)

2 studies, N >12,000 Hettema et al. 2001 (meta-analysis)

Kendler et al. 1992, 2001b Kendler et al. 1992, 2001b Kendler et al. 1992, 2001b van Grootheest et al. 2005 (review)

Anorexia nervosa Bulimia nervosa Alcohol dependence

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