Individual differences in trait negative affect are important predictors of vulnerability for a spectrum of health-related disorders including depression, anxiety, and cardiovascular disease (1
). As such, identifying biological variables contributing to the emergence of such interindividual variability holds great potential for elucidating both the etiology and pathophysiology of these disorders. Moreover, certain biological variables may offer clinical utility by serving as predictive markers of increased disease risk. Converging evidence from rodent and nonhuman primate as well as extensive human research has implicated variability in serotonin (5-HT) neurotransmission as a key predictor of individual differences in multiple, overlapping behavioral constructs related to trait negative affect (3
). Research employing pharmacologic challenge of the 5-HT system (via specific receptor agonism/antagonism or general reuptake blockade), for example, has indicated that these manipulations can modulate peripheral stress responses and subjective negative affect (4
). These and other findings have subsequently spurred intensive efforts to identify genetic polymorphisms in 5-HT subsystems, which ultimately control the regulation of 5-HT neurotransmission as a function of both homeostatic drive and environmental feedback, that predict trait negative affect, as well as differentiate relative risk for disease.
Of particular importance in these efforts has been the 5-HT transporter (5-HTT), which is responsible for the active clearance of synaptic 5-HT and thus regulation of presynaptic and postsynaptic 5-HT receptor stimulation. In 1996, Lesch and colleagues (5
) identified a relatively common functional promoter polymorphism in the human 5-HTT gene (SLC6A4
). The so-called 5-HTT gene linked polymorphic region, or 5-HTTLPR, is typically defined by two variable nucleotide tandem repeat elements, a short (S) allele comprising 14 copies of a 20-23 base pair repeat unit and a long (L) allele comprising 16 copies. Although initial in vitro and in vivo assays revealed relatively diminished 5-HTT density associated with the S allele, recent work has indicated that more complex mechanisms (e.g., regional up- and down-regulation of specific 5-HT receptors) and not altered 5-HTT density may mediate the long-term impact of the 5-HTTLPR on 5-HT neurotransmission (7
). Regardless of the underlying mechanisms of action, a modest association has been reported between the 5-HTTLPR S allele and relatively increased trait negative affect (8
). Moreover, the 5-HTTLPR S allele has been associated with relatively increased risk for depression in the context of environmental adversity (12
), a relationship that may be mediated by increased neuroticism (16
), a psychometrically robust index of trait negative affect.
Although positive associations between the 5-HTTLPR S allele and increased trait negative affect or risk for depression have not been consistently demonstrated across studies (17
), recent data from the emerging field of imaging genetics (20
) has provided apparently consistent evidence for a link between the 5-HTTLPR S allele and relatively heightened amygdala activation to emotional stimuli relative to neutral stimuli, a key neural process underlying the generation of behavioral and physiologic arousal to environmental threat. Since the original demonstration of this relationship (22
) using functional magnetic resonance imaging (fMRI) in 2002, several studies have reported a link between increased amygdala activation and the 5-HTTLPR S allele using a variety of neuroimaging technologies (i.e., fMRI, positron emission tomography [PET], perfusion MRI), provocative stimuli (e.g., emotional facial expressions, pictures and words) and subject populations (e.g., controls as well as patients with social phobia, panic disorder, and major depression). The collective results of these studies suggest that relatively heightened amygdala activation to environmental threat may mediate the association between the 5-HTTLPR S allele and increased trait negative affect, as well as risk for mood and anxiety disorders, especially in response to chronic or severe stress. Recent evidence of traitlike stability for individual differences in amygdala activation measured with fMRI over both short (2- and 8-week) and long (> 1 year) intervals (23
) further underscores the possible and potentially unique role of the amygdala in mediating effects of the 5-HTTLPR on enduring aspects of temperament and personality.
A perennial difficulty in the field of psychiatric genetics is nonreplication of initially promising findings, in part due to the small magnitude of single gene effects on complex behavioural phenotypes (25
). Although endophenotype measures, such as amygdala activation, may offer larger effect sizes, this assumption requires further exploration, and the small sample sizes typical of studies of this kind raise the possibility of Type I error (26
). Even in the case of associations that have been replicated with reasonable robustness, there is evidence that the first published study often suggests an effect size that in time proves to be an overestimate of the true effect size (27
). Publication bias, in which findings that fail to achieve statistical significance or that are in the opposite direction to that which is predicted are less likely to be published, may also undermine the integrity of published data (28
). Meta-analysis is an increasingly common method for addressing these issues, allowing an assessment of the overall strength of evidence for association and formal testing for evidence of publication bias (25
), as well as the exploratory investigation of possible sources of between-study heterogeneity such as moderation by measurement instrument (29
In light of these findings and their potential to inform neurogenetic pathways for disease risk, we were motivated to evaluate formally the reported associations between amygdala activation and the 5-HTTLPR S allele and the likely magnitude of this relationship using meta-analytic techniques. We also tested for possible publication bias, and explored possible moderating influences on any association, such as sample ancestry.