Genotype groups did not differ significantly on any self-reported variables including EN (all Ps > 0.07), CTQ total (all Ps > 0.07), gender ratio (all Ps > 0.25) or age (all Ps > 0.5; Table 2). Consistent with previous research the task reliably recruited threat-related reactivity of the dorsal and ventral amygdala (Fig. 1a,b) (Brown et al. 2005, 2006; Manuck et al. 2007; Neumann et al. 2006). Additionally, consistent with our previous report in a larger sample from TAOS, both right ventral and dorsal ROIs exhibited a positive main effect of EN score (F1,137 = 5.87, P = 0.017; F1,137 = 4.55, P = 0.035; respectively) (Bogdan et al. 2012).
GLM revealed significant EN-by-genotype interaction effects on both the right and left dorsal amygdala ROIs (see Table 2), which survived SNPspD correction for multiple testing (P < 0.019). However, no significant interaction effects were observed on ventral amygdala ROIs after accounting for SNPspD correction (all Fs5,133 < 4.57, all Ps > 0.034). FKBP5 SNPs rs7748266 (F5,133 = 6.58, = 0.011), rs1360780 (F5,133 = 10.31, P = 0.002), rs9296158 (F5,133 = 9.99, P = 0.002), rs3800373 (F5,133 = 9.16, P = 0.003) and rs9470080 (F5,133 = 6.59, P = 0.011) had significant interaction effects on right dorsal amygdala reactivity (see Fig. 2a–e); while SNPs rs9394309 (F5,133 = 6.39, P = 0.013) and rs7748266 (F5,133 = 8.51, P = 0.004) had significant interaction effects on left dorsal reactivity (see Fig. 3a,b). These effects survived a multiple SNP comparison generated by SNPspD (P < 0.019) and four SNPs (rs7748266, rs1360780, rs9296158 and rs3800373) survived an additional Bonferroni correction for multiple ROI comparisons (P < 0.0048). However, there was no significant main effect of genotype for any SNP on dorsal (see Table 2) or ventral amygdala ROIs (all Ps > 0.06). Exploratory haplotype analyses revealed that both the five-SNP haplotype block generated from Haploview (rs9296158, rs7748266, rs1360780, rs9394309 and rs9470080) and the four-SNP haplotype block created post hoc with SNPs showing the most significant interaction effects (rs3800373, rs9296158, rs1360780 and rs7748266), interacted with EN to predict right dorsal amygdala reactivity (Haploview: F5,133 = 6.59, P = 0.011; Fig. 4a; post hoc composition: F5,133 = 9.99, P = 0.002; Fig. 4b). Both haplotype analyses are significant after Bonferroni correction for multiple haplotype comparisons (P = 0.025). Results using a whole amygdala ROI (Figure S1) were similar to those seen in the dorsal subregion (Table S1). Additionally, similar results in the dorsal amygdala were obtained when using the total CTQ score (Table S1). We also tested the interactions including subjects (n = 17) with a current or past diagnosis of a mood or anxiety disorder. The results were essentially unchanged; ENxFKBP5 interactions emerged for the same SNPs predicting right (rs7748266, rs9296158, rs1360780, rs3800373 and rs9470080) and left (rs7748266 and rs9394309) dorsal amygdala reactivity (all Fs5,150 > 6.4, all Ps < 0.012).
Figure 4. FKBP5 haplotypes showing significant interaction effects with emotional neglect on right dorsal amygdala reactivity: (a) five-SNP haplotypes (rs9296158, rs7748266, rs1360780, rs9394309 and rs9470080) generated from Haploview (P = 0.011). Subjects were categorized based on the presence of the GCCAC haplotype (i.e. 0, 1 or 2 copies), which is comprised of ‘non-risk’ alleles. (b) Four-SNP haplotypes (rs3800373, rs9296158, rs1360780 and rs7748266) constructed from SNPs showing most significant interaction effects (P = 0.002). Subjects were categorized based on the presence of the TGCC haplotype (i.e. 0, 1 or 2 copies), which is comprised of ‘non-risk’ alleles. Plots show relationship between EN and amygdala BOLD separated by haplotype group.
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