Abstract
It is not known how 5-HTTLPR genotype × childhood adversity (CA) interactions that are associated with an increased risk for affective disorders in population studies operate at the neural systems level. We hypothesized that healthy adolescents at increased genetic and environmental risk for developing mood disorders (depression and anxiety) would demonstrate increased amygdala reactivity to emotional stimuli compared to those with only one such risk factor or those with none. Participants (n = 67) were classified into one of 4 groups dependent on being homozygous for the long or short alleles within the serotonin-transporter-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene and exposure to CA in the first 11 years of life (present or absent). A functional magnetic resonance imaging investigation was undertaken which involved viewing emotionally-salient face stimuli. In addition, we assessed the role of other variables hypothesized to influence amygdala reactivity, namely recent negative life-events (RNLE) assessed at ages 14 and 17, current anxiety symptoms and psychiatric history. We replicated prior findings demonstrating moderation by gene variants in 5-HTTLPR, but found no support for an effect of CA on amygdala reactivity. We also found a significant effect of RNLE aged 17 with amygdala reactivity demonstrating additive, but not interactive effects with 5-HTTLPR. A whole-brain analysis found a 5-HTTLPR × CA interaction in the lingual gyrus whereby CA appears to differentially modify neural reactivity depending on genotype. These results demonstrate that two different forms of environmental adversities interplay with 5-HTTLPR and thereby differentially impact amygdala and cortical reactivity.
Highlights
The amygdala is a neural region fundamental for emotion processing (Adolphs et al, 2005; Tye et al, 2011)
Through meta-analysis, it has been demonstrated that individuals carrying the less efficient short allele of the 5-HTTLPR, the gene variant associated with increased susceptibility for affective disorders, reliably demonstrate increased amygdala reactivity when exposed to negative or arousing environmental stimuli (Munafo et al, 2008; Murphy et al, 2012)
In relation to theoretical models of 5-HTTLPR and amygdala reactivity, these results suggest a valence-general, and both environmental and genetically mediated phasic amygdala reactivity, rather than the tonic model of genetically mediated amygdala activation proposed by Canli and others (Canli and Lesch, 2007; Canli et al, 2005, 2006; Heinz et al, 2007) whereby there is a decrease in amygdala activation to neutral faces
Summary
The amygdala is a neural region fundamental for emotion processing (Adolphs et al, 2005; Tye et al, 2011). The most studied genetic moderator of amygdala reactivity has been allelic variation in the serotonin-transporter-linked-promoter region (5-HTTLPR) of the SLC6A4 gene (Alexander et al, 2012; Bertolino et al, 2005; Brown and Hariri, 2006; Canli et al, 2005, 2006; Dannlowski et al, 2008, 2010; Drabant et al, 2012; Friedel et al, 2009; Furman et al, 2011; Furmark et al, 2004, 2009; Gillihan et al, 2010; Hariri et al, 2002, 2005; Heinz et al, 2005, 2007; Klucken et al, 2012; Kobiella et al, 2011; Lau et al, 2009; Lemogne et al, 2011; Lonsdorf et al, 2011; Schardt et al, 2010; Smolka et al, 2007; von dem Hagen et al, 2011; Wolfensberger et al, 2008). Through meta-analysis, it has been demonstrated that individuals carrying the less efficient short allele of the 5-HTTLPR, the gene variant associated with increased susceptibility for affective disorders, reliably demonstrate increased amygdala reactivity when exposed to negative or arousing environmental stimuli (Munafo et al, 2008; Murphy et al, 2012)
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