models (Chang, Bray, et al., 2008; Bear, Dolen, et al., 2008; Chahrour and Zoghbi, 2007; Dolen, Osterweil, et al., 2007; Giacometti, Luikenhuis, et al., 2007; Guy, Gan, et al., 2007). Animal models have also successfully linked risk genes with disturbances in particular molecular pathways that may predispose to the development of more complex, polygenic disorders, such as depression (Cryan and Holmes, 2005; Urani, Chourbaji, and Gass, 2005), anxiety disorders (Cryan and Holmes, 2005), obsessive compulsive disorder (Joel, 2006), autism (Moy and Nadler, 2008), schizophrenia (O’Tuathaigh, Babovic, et al., 2007), and substance abuse (Kalivas, Peters, and Knackstedt, 2006).

Despite the challenge of studying the role of genes in the etiology of MEB disorders, advances in technology continue to make large-scale genotyping more feasible and affordable, and the combination of human genetics studies and approaches using animal models has proven to be informative in identifying genes of risk in multifactorial, complex non-psychiatric disorders, such as asthma (Moffatt, 2008) and diabetes (Florez, 2008); they will undoubtedly make important contributions in psychiatric genetics in coming years.

Gene–Environment Interactions and Correlations

Most complex behaviors and the most common forms of MEB disorders are likely to arise from a combination of multiple interacting genetic and environmental influences (Caspi and Moffitt, 2006; Rutter, Moffitt, and Caspi, 2006). The effect of a common genetic variant in altering the risk for a disorder, for example, is likely to be conditioned heavily by the experiences of a developing child, just as the effects of experience in producing a disorder are likely to be conditioned by the genetic background that the child inherits from his or her parents (Rutter, Moffitt, and Caspi, 2006; Thapar, Harold, et al., 2007). These so-called gene–environment (GxE) interactions can confer both risk and protective effects on the child relative to the effects of either the genetic or environmental influences in isolation.

A number of interactions between specific identified genes and specific environmental risk factors have been demonstrated in MEB disorders (Rutter, Moffitt, and Caspi, 2006). For example, a landmark prospective epidemiological study found that the number of copies an individual carries of the short variant of a region of the serotonin transporter gene (5-HTTLPR) significantly increases, in a dose-dependent fashion, the risk for developing depressive symptoms, major depressive disorder, and suicidality—but only in the context of adverse or stressful early life experiences (Caspi, Sugden, et al., 2003) (see Figure 5-1). Similarly, a polymorphism in the gene that encodes monoamine oxidase A (MAOA), an enzyme that metabolizes neurotransmitters, moderates the effect of maltreatment on developing antisocial



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