A Common Polymorphism in a Williams Syndrome Gene Predicts Amygdala Reactivity and Extraversion in Healthy Adults

Abstract

Background: Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior.

Methods: Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students.

Results: The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men.

Conclusions: A common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety.

Keywords: Amygdala; Emotion; Extraversion; GTF2I; Williams syndrome; fMRI.

Figure 1. GTF2i rs13227433 genotype predicts left amygdala reactivity to threat

Parameter estimates for reactivity to threat were extracted from a functional cluster within the anatomically defined left amygdala region of interest for the contrast of Angry and Fearful blocks > Control blocks. Error bars represent 1 standard error.

Figure 2. Decreased amygdala reactivity to threat predicts higher extraversion in women

Parameter estimates for reactivity to threat were extracted from a functional cluster within the anatomically defined left amygdala region of interest for the contrast of Angry and Fearful blocks > Control blocks.

Figure 3. Full mediation model testing indirect effect of rs13227433 genotype on warmth, mediated by left amygdala reactivity to threat

Parameters for the gene to brain path were constrained to be equal for men and women. The direct effect was modeled by including genotype as a predictor in the regression for warmth, in addition to the mediator (threat-related amygdala reactivity) and covariates. αβ = indirect effect, SE=standard error, LLCI=95% lower-limit confidence interval; ULCI=95% upper-limit confidence interval.