Variation in Genotype

Another methodological strategy is to relate the behavior of interest to genetic polymorphisms that have independently been associated with serotonergic function (Manuck et al., 2006). Though a large number of genes relate to serotonergic function (Martinowich & Lu, 2007), most of the genetic research discussed here examined the gene that codes the serotonin transporter. The transporter plays a key role in serotonergic transmission by facilitating reuptake of serotonin from the synaptic cleft (Heils et al., 1996). Indeed, under normal circumstances, this is the principal mechanism for actively clearing serotonin from the synaptic cleft.

Transcriptional activity of the transporter gene is believed to be influenced by (or at least associated with) a repetitive sequence in a polymorphic region called 5-HTTLPR, which has a short version and a long version (i.e., which has more repetitions). A variety of indirect evidence links this polymorphism to serotonergic function, though it is important to note that the evidence is not completely uniform (disconfirming findings have been reported, e.g., by Mann et al., 2000, and van Dyck et al., 2004).

Supportive evidence includes the following: The long version is associated in vitro with higher transcription efficiency than that of the short one. In human lymphoblast cells, for example, the long– long combination was linked to serotonin uptake 1.9 to 2.2 times that of the short–short or long–short combination, which had comparable serotonin uptake (Lesch et al., 1996). The alleles have also shown similar ratios in binding levels, in imaging measures of radioligand binding to 5-HTT in vivo (Heinz et al., 2000) and in postmortem calculations of 5-HTT density (Little et al., 1998). Neuroimaging studies in humans and nonhuman primates have found an inverse relation between 5-HTT availability and cerebrospinal fluid concentrations of a 5-HT metabolite (Heinz et al., 2002), suggesting that the 5-HTTLPR is functional and influences serotonergic neurotransmission. One recent study found carriers of the short allele had twice the turnover of brain serotonin as those without the short allele (Barton et al., 2008). Of particular importance, in some of the literatures to be discussed, the 5-HTTLPR polymorphism has been associated with outcomes that resemble those obtained through direct manipulation of the serotonergic system. Thus, although there remain questions about causal mechanisms, the short allele is widely viewed as a marker of low serotonergic function (e.g., Canli & Lesch, 2007).

Two variants of the long allele have been identified relatively recently (Hu, Zhu, Lipsky, & Goldman, 2004). The expression of one variant is comparable with that of the short allele, and the two long variants behave differently in response to pharmacological challenge (Hu et al., 2005; Neumeister et al., 2006). Such findings encourage closer attention to variability in this polymorphism (this polymorphic region may have as many as 10 variants in humans; Nakamura, Ueno, Sano, & Tanabe, 2000). Further, polymorphisms at other sites on this gene also appear to have functional effects on transporter expression (Kraft et al., 2007). More generally, it is important to acknowledge that the genetic association studies we describe here evaluate correlations between a phenotype and the single marker that is under study, rather than a causal link.

Nonetheless, most published work on the serotonin transporter is limited to comparisons on 5-HTTLPR. Most published work is further limited to comparisons that involve the long and short allele without further differentiation. Thus, in this article, mention of polymorphisms in the serotonin transporter gene always refers specifically to 5-HTTLPR and primarily to short- versus long-allele carriers. A few studies that do go beyond this are noted later on.

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