BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels

Abstract

Brain-derived neurotrophic factor (BDNF) has been implicated in multiple aspects of brain function including regulation of serotonin signaling. The BDNF val66met polymorphism (rs6265) has been linked to aspects of serotonin signaling in humans but its effects are not well understood. To address this, we evaluated whether BDNF val66met was predictive of a putative marker of brain serotonin levels, serotonin 4 receptor (5-HT4 ) binding assessed with [11C]SB207145 positron emission tomography, which has also been associated with the serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We applied a linear latent variable model (LVM) using regional 5-HT4 binding values (neocortex, amygdala, caudate, hippocampus, and putamen) from 68 healthy humans, allowing us to explicitly model brain-wide and region-specific genotype effects on 5-HT4 binding. Our data supported an LVM wherein BDNF val66met significantly predicted a LV reflecting [11C]SB207145 binding across regions (P = 0.005). BDNF val66met met-carriers showed 2-9% higher binding relative to val/val homozygotes. In contrast, 5-HTTLPR did not predict the LV but S-carriers showed 7% lower neocortical binding relative to LL homozygotes (P = 7.3 × 10(-6)). We observed no evidence for genetic interaction. Our findings indicate that BDNF val66met significantly predicts a common regulator of brain [11C]SB207145 binding, which we hypothesize reflects brain serotonin levels. In contrast, our data indicate that 5-HTTLPR specifically affects 5-HT4 binding in the neocortex. These findings implicate serotonin signaling as an important molecular mediator underlying the effects of BDNF val66met and 5-HTTLPR on behavior and related risk for neuropsychiatric illness in humans.

Keywords: 5-HT4 receptor; 5-HTTLPR; BDNF; positron emission tomography; serotonin.

Figure 1

Latent variable model of genetic effects on [¹¹C]SB207145 binding. Our final LVM is depicted with model paths. Green boxes indicate observed predictors. The red circle reflects the latent variable (u). Orange boxes represent measured log‐transformed regional [¹¹C]SB207145 binding potential values. Age, sex, BMI, weight‐adjusted (w.a.) injected mass, and BDNF val66met genotype all map onto the latent variable whereas 5‐HTTLPR, scanner type, and an age effect on caudate directly affect regional binding potential values. BDNF val66met val/val and 5‐HTTLPR LL groups are reference for respective genotype parameter estimates. Orange hatched lines between (1) caudate and putamen and (2) amygdala and hippocampus indicate additional shared correlation; circular red and orange hatched lines reflect error estimates included in the model. The parameter estimate, β, for each model path is noted in respective boxes (95% confidence intervals indicated for estimates between latent variable and regional binding estimates). Significance of parameters estimates, P, is also noted. All regions loaded significantly onto the latent variable (all factor loadings: P < 9.8 × 10⁻⁵).

Figure 2

BDNF val66met effects on [¹¹C]SB207145 binding. BDNF met‐carriers showed higher [¹¹C]SB207145 binding potential (BP_ND) in all regions evaluated. However, only effects in neocortex were statistically significant (see Table 2 for model estimates). Gray dots represent individual residuals of log‐transformed BP_ND values, adjusted for age, sex, weight‐adjusted injected mass, scanner, BMI, and 5‐HTTLPR genotype. Black lines represent group mean and corresponding 95% confidence intervals. VV = BDNF val66met val/val genotype, MX = BDNF val66met met‐carrier.

Figure 3

5‐HTTLPR effects on [¹¹C]SB207145 binding. 5‐HTTLPR S‐carriers showed significantly lower [¹¹C]SB207145 binding potential (BP_ND) within neocortex compared to LL homozygotes. However, effects in all other regions were not statistically significant (see Table 2 for model estimates). Gray dots represent individual residuals of log‐transformed BP_ND values, adjusted for age, sex, weight‐adjusted injected mass, scanner, BMI, and BDNF val66met genotype. Black lines represent group mean and corresponding 95% confidence intervals. LL = 5‐HTTLPR LL genotype, SX = 5‐HTTLPR S‐carriers.

Figure 4

BDNF val66met by age interaction effect on [¹¹C]SB20715 binding. Within a post hoc analysis, we observed evidence that BDNF val66met moderated the age effect on [¹¹C]SB207145 binding. This effect is visualized here for neocortex (interaction effect: 0.0049 [0.0024, 0.0073], P = 1.1 × 10⁻⁴). Black and gray dots represent val/val individuals and met‐carriers, respectively. Lines and shading represent genotype slope estimates and 95% confidence intervals, respectively. Data are plotted as log‐transformed neocortex [¹¹C]SB207145 binding values, adjusted for sex, weight‐adjusted injected mass, scanner, BMI and 5‐HTTLPR genotype. Notably, our data suggest that met‐carriers show higher binding through adulthood compared to val/val individuals.