serotonin system (5-HT). The neurotransmitter serotonin exerts effects on a broad range of physiological functions, such as emotions, sleep, circadian rhythm, thermoregulation, appetite, aggression, sexual behavior, pain sensitivity, and sensorimotor reactivity (e.g., Lucki, 1998; Neumeister, Young, and Strastny, 2004). Deficits in the central 5-HT system, such as reduced 5-HT concentrations, impaired uptake function of the 5-HT transporter, altered 5-HT receptor binding, and tryptophan depletion, have been linked to a number of psychological problems and psychiatric disorders, including depression (Neumeister, Young, and Strastny, 2004).

A number of studies have investigated the role of genetic polymorphisms in the serotonin-related genes in the etiology of depression. Currently, the serotonin transporter (5-HTTLPR) gene is the most promising one. Importantly, Caspi et al. (2003) and Kendler et al. (2005) found that individuals with one or two copies of the short allele of 5-HTTLPR experienced more depressive symptoms and higher rates of major depressive disorder in response to stressful life events than individuals who are homozygous for the long allele. These studies are especially noteworthy for their indication that genetic effects on depression may be observed only under conditions of exposure to stressors (see reviews by Uher and McGuffin, 2008; Zammit and Owen, 2006). The effects of the serotonin transporter polymorphism implicated in depression in response to stressful life events may be manifested behaviorally as dysfunctional emotionality in response to stress.

As an illustration of the complex transactions among brain functions, genes, and neurotransmitter systems, Hariri et al. (2005) used neuroimaging techniques to explore how individuals with different polymorphisms of the 5-HTTLPR gene responded to an amygdala activation task involving perception of fearful and angry faces. They found that normal, never-depressed individuals who had the short allele form of the 5-HTTLPR gene showed amygdala hyperreactivity in response to the emotion-arousing stimuli compared with other groups. The results suggest that the serotonin transporter polymorphism is linked to the brain’s processing of emotional threat information. The study is noteworthy for helping to shed further light on neurobiological mechanisms by which stressful environmental experiences eventuate in depression in some people but not others.

In addition to the 5-HTTLPR polymorphisms, numerous other serotonin system genes have been studied as well as those known to affect the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and other brain regions. Meta-analytic studies of candidate genes and molecular genetic genome-wide association studies are increasing throughout the world, but it has been noted by a recent large-sample genome-wide association study of the high heritable human trait of height that they are likely to show what has long been predicted in quantitative genetics: Any relevant



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