5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression

Abstract

Carriers of the short allele of a functional 5′ promoter polymorphism of the serotonin transporter gene have increased anxiety-related temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdala-cingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression.

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Figure 1: Thresholded (P < 0.05) statistical maps restricted to the limbic cortex and amygdala illustrating gray matter volume reductions of s allele carriers in comparison to l/l genotype (n = 114).
Figure 2: Structural data illustrating peak volume changes and results of structural covariance analyses (n = 114).
Figure 3: Statistical functional connectivity maps between bilateral amygdala and perigenual anterior cingulate cortex representing degree of functional coupling between these structures (n = 94).
Figure 4: Functional connectivity between the subgenual cingulate and amygdala is dissociated by genotype and significantly explains harm avoidance scores, whereas other functional or structural measures do not.

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Acknowledgements

We thank A. Goldman and P. Fisher for technical assistance and H. S. Mayberg for comments on the manuscript. Furthermore, we thank T.E. Goldberg for providing psychological data and J.H. Callicott for support of data acquisition. This work was supported by the US National Institute of Mental Health Intramural Research Program.

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Correspondence to Daniel R Weinberger.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Unmasked and thresholded (t > 2) statistical map of reported subgenual anterior cingulate cortex volume reduction in S carriers in comparison to LL genotype. Slices in axial view are displayed from superior (top left corner) to inferior (bottom right corner) in 1 mm steps. Color scale represents t-scores. This map highlights the spatial dimension of volume reductions found in S carriers within the subgenual anterior cingulate cortex, which is the location of maximal volume reductions in S carriers in comparison to LL genotype. (JPG 32 kb)

Supplementary Figure 2

Spatial relationship between regions of interest (ROIs) used in a study by Heinz et al.1 and our study. Both ROIs are projected on the left hemisphere and do not cover the same medial prefrontal brain regions. It is noteworthy that the area of the subgenual cingulum, where we found maximal statistical differences is not covered by the ROI used by Heinz et al. The ROI used by Heinz et al was reconstructed by using a 36 mm diameter sphere centered between the genu of the corpus callosum and the anterior pole (x, y, z = 0, 52, -3) as reported 1. In our study, we used a ROI, which was based on observed volumetric effects in S allele carriers in comparison to LL genotype (see methods section for details). Axis dimensions represent Talairach space. (JPG 20 kb)

1. Heinz, A. et al. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 8, 20-1 (2005).

Supplementary Figure 3

Statistical functional connectivity maps between bilateral amygdala and the ROI used by Heinz et al.1 display degree of functional coupling between these structures (n = 94) with respect to genotype (color bar representing t-scores). Blue areas (negative t-scores) indicate that 5-HTTLPR S allele carriers show higher functional coupling between amygdala and this spherical ROI than LL individuals similar to findings reported by Heinz et al. 1. Positive t-scores represent the inverse relationship. Statistics remain non-significant after correction for multiple comparisons within this ROI. (JPG 28 kb)

1. Heinz, A. et al. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 8, 20-1 (2005).

Supplementary Figure 4

Diagram summarizing functional connectivity analyses and effects of genotype in context of available knowledge about anatomical pathways. Carriers of the S allele show a marked diminished functional connectivity between amygdala and anterior subgenual cingulate cortex in comparison to LL genotype; amygdala-supragenual anterior cingulate connectivity is also reduced, but less so. Genotype had no effect on subgenual-supragenual anterior cingulate connectivity. The direction of arrows is based on anatomical tracing studies of principle projection paths. (JPG 57 kb)

Supplementary Table 1

Correlation analysis of regional volume and BOLD signal (n = 26). (PDF 54 kb)

Supplementary Table 2

Functional connectivity between subgenual (reference region) and supragenual anterior cingulate cortex (target region). (PDF 70 kb)

Supplementary Table 3

Correlation analysis of imaging data with behavioral data (n = 26). (PDF 56 kb)

Supplementary Table 4

Functional connectivity between subgenual cingulate (reference region) and bilateral ventromedial prefrontal regions (target region) reported by Heinz et al.1 (PDF 72 kb)

Supplementary Table 5

Demographic information for subjects included in structural (n = 114) and functional (n = 94) analyses. (PDF 59 kb)

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Pezawas, L., Meyer-Lindenberg, A., Drabant, E. et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 8, 828–834 (2005). https://doi.org/10.1038/nn1463

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