Exploring the Impact of BDNF Val66Met Genotype on Serotonin Transporter and Serotonin-1A Receptor Binding

Abstract

BackgroundThe brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) may impact on the in-vivo binding of important serotonergic structures such as the serotonin transporter (5-HTT) and the serotonin-1A (5-HT1A) receptor. Previous positron emission tomography (PET) studies on the association between Val66Met and 5-HTT and 5-HT1A binding potential (BPND) have demonstrated equivocal results.MethodsWe conducted an imaging genetics study investigating the effect of Val66Met genotype on 5-HTT or 5-HT1A BPND in 92 subjects. Forty-one subjects (25 healthy subjects and 16 depressive patients) underwent genotyping for Val66Met and PET imaging with the 5-HTT specific radioligand [11C]DASB. Additionally, in 51 healthy subjects Val66Met genotypes and 5-HT1A binding with the radioligand [carbonyl-11C]WAY-100635 were ascertained. Voxel-wise and region of interest-based analyses of variance were used to examine the influence of Val66Met on 5-HTT and 5-HT1A BPND.ResultsNo significant differences of 5-HTT nor 5-HT1A BPND between BDNF Val66Met genotype groups (val/val vs. met-carrier) were detected. There was no interaction between depression and Val66Met genotype status.ConclusionIn line with previous data, our work confirms an absent effect of BDNF Val66Met on two major serotonergic structures. These results could suggest that altered protein expression associated with genetic variants, might be compensated in vivo by several levels of unknown feedback mechanisms. In conclusion, Val66Met genotype status is not associated with changes of in-vivo binding of 5-HTT and 5-HT1A receptors in human subjects.

Epistasis of HTR1A and BDNF risk genes alters cortical 5-HT1A receptor binding: PET results link genotype to molecular phenotype in depression

“…All healthy subjects from three previously reported samples collected between 2004 and 2016 for who genotypes for rs6265 and rs6295 were available were pooled for this analysis 7,35,41,45,46 . Due to the lack of a patient sample of adequate size to investigate genetic interaction, only healthy subjects were considered.…”

“…Concerning rs6265 of BDNF , several targets of the serotonergic system were investigated, including serotonin transporter (SERT), 5-HT 1A , and 2A receptor, as well as 5-HT 4 receptor binding. The less common A allele resulting in methionine was suggested to decrease 5-HT 1A receptor binding measured by free plasma concentration binding potential (BP F ) while other studies reported negative results based on BP ND 35–37 . Recently, the A allele was also associated with increased SERT binding in a large cohort of healthy subjects, while earlier studies reported gender-dependent lower binding in A-carriers or no differences 35,36,38 .…”

The influence of the rs6295 gene polymorphism on serotonin-1A receptor distribution investigated with PET in patients with major depression applying machine learning

“…This is a pooled sample derived from previous studies, however, all genetic data regarding rs6295 are unpublished. 48 , 49 , 50 , 51 , 52 , 53 Eighty-one subjects aged 18–65 years were enrolled in this neuroimaging genetics study with a cross-sectional design. Sixty-two healthy subjects (40 female) and 19 acutely depressed patients (6 female) diagnosed according to Structured Clinical Interview for DSM-IV type disorders (SCID I+II) were included.…”

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

“…70 In the human brain, the BDNF Met allele was associated with reduced 5-HT 1A binding in 1 study, 71 but not others. 72,73 In a recent study, 3 or more combined HTR1A and BDNF risk alleles associated increase 5-HT 1A receptor binding in cortical subregions. 74 In contrast, the COMT Val158Met rs4680 genotype oppositely altered the rs6295 association with interferon-induced depression.…”