BDNF val66met association with serotonin transporter binding in healthy humans

P M Fisher, B Ozenne, C Svarer, D Adamsen, S Lehel, W F C Baaré, P S Jensen, G M Knudsen, P M Fisher, B Ozenne, C Svarer, D Adamsen, S Lehel, W F C Baaré, P S Jensen, G M Knudsen

Abstract

The serotonin transporter (5-HTT) is a key feature of the serotonin system, which is involved in behavior, cognition and personality and implicated in neuropsychiatric illnesses including depression. The brain-derived neurotrophic factor (BDNF) val66met and 5-HTTLPR polymorphisms have predicted differences in 5-HTT levels in humans but with equivocal results, possibly due to limited sample sizes. Within the current study we evaluated these genetic predictors of 5-HTT binding with [11C]DASB positron emission tomography (PET) in a comparatively large cohort of 144 healthy individuals. We used a latent variable model to determine genetic effects on a latent variable (5-HTTLV), reflecting shared correlation across regional 5-HTT binding (amygdala, caudate, hippocampus, midbrain, neocortex, putamen and thalamus). Our data supported a significant BDNF val66met effect on 5-HTTLV such that met-carriers showed 2-7% higher subcortical 5-HTT binding compared with val/val individuals (P=0.042). Our data did not support a BDNF val66met effect in neocortex and 5-HTTLPR did not significantly predict 5-HTTLV. We did not observe evidence for an interaction between genotypes. Our findings indicate that met-carriers have increased subcortical 5-HTT binding. The small difference suggests limited statistical power may explain previously reported null effects. Our finding adds to emerging evidence that BDNF val66met contributes to differences in the human brain serotonin system, informing how variability in the 5-HTT level emerges and may represent an important molecular mediator of BDNF val66met effects on behavior and related risk for neuropsychiatric illness.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Latent variable model. Blue hatched boxes represent observed predictors. The green oval represents the estimate latent variable, 5-HTTLV. Orange solid boxes represent measured regional 5-HTT BPND values. Lines denote included model paths. Although not indicated, MRI scanner and PET scanner are modeled as predictors of regional 5-HTT BPND. BDNF val66met val/val and 5-HTTLPR LALA are reference groups for respective parameter estimates. Hatched lines between regions indicate additional shared correlation. Hatched circles indicate error estimates included. Parameter estimates, β, for each model path indicated in respective boxes with either 95% confidence interval or P-value noted. All regions significantly loaded on the latent variable (all factor loadings: P<10−12). 5-HTT, serotonin transporter; BDNF, brain-derived neurotrophic factor; MRI, magnetic resonance imaging; PET, positron emission tomography.
Figure 2
Figure 2
Representative BDNF val66met effects on thalamus and neocortex 5-HTT BPND. BDNF val66met met-carriers showed higher 5-HTT BPND in thalamus and other subcortical regions but not neocortex (see Table 2 for model estimates). Orange dots represent 144 individual 5-HTT BPND values, adjusted for age, MRI scanner and PET scanner. Blue lines represent group mean±1 s.d. 5-HTT, serotonin transporter; BDNF, brain-derived neurotrophic factor; MRI, magnetic resonance imaging; PET, positron emission tomography.

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