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

Alexander Kautzky,Cecile Philippe,Christoph Kraus,Annette M Hartmann,Pia Baldinger-Melich,Wolfgang Wadsak,Gregor Gryglewski,Georg S Kranz,Thomas Vanicek,Andreas Hahn,Dan Rujescu,Rupert Lanzenberger,Siegfried Kasper,Gregory M James,Markus Mitterhauser

doi:10.1038/s41398-018-0308-2

Alexander Kautzky, Cecile Philippe + Show 13 more

Open Access

https://doi.org/10.1038/s41398-018-0308-2

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Abstract

Alterations of the 5-HT1A receptor and BDNF have consistently been associated with affective disorders. Two functional single nucleotide polymorphisms (SNPs), rs6295 of the serotonin 1A receptor gene (HTR1A) and rs6265 of brain-derived neurotrophic factor gene (BDNF), may impact transcriptional regulation and expression of the 5-HT1A receptor. Here we investigated interaction effects of rs6295 and rs6265 on 5-HT1A receptor binding. Forty-six healthy subjects were scanned with PET using the radioligand [carbonyl-11C]WAY-100635. Genotyping was performed for rs6265 and rs6295. Subjects showing a genotype with at least three risk alleles (G of rs6295 or A of rs6265) were compared to control genotypes. Cortical surface binding potential (BPND) was computed for 32 cortical regions of interest (ROI). Mixed model was applied to study main and interaction effects of ROI and genotype. ANOVA was used for post hoc analyses. Individuals with the risk genotypes exhibited an increase in 5-HT1A receptor binding by an average of 17% (mean BPND 3.56 ± 0.74 vs. 2.96 ± 0.88). Mixed model produced an interaction effect of ROI and genotype on BPND and differences could be demonstrated in 10 ROI post hoc. The combination of disadvantageous allelic expression of rs6295 and rs6265 may result in a 5-HT1A receptor profile comparable to affective disorders as increased 5-HT1A receptor binding is a well published phenotype of depression. Thus, epistasis between BDNF and HTR1A may contribute to the multifactorial risk for affective disorders and our results strongly advocate further research on this genetic signature in affective disorders.

Highlights

The monoamine neurotransmitter serotonin has an essential role in behavior and cognition[1]
An interaction effect could be demonstrated for regions of interest (ROI) and genotype (F = 1.567, p = 0.048, Bonferroni corrected for the number of models and effects)
Investigating a large sample of 46 healthy individuals with [carbonyl-11C]WAY-100635, we observed higher 5HT1A receptor binding by an average of 17% in the risk group with a genotype of 3 or more putative risk alleles of the two SNPs, rs6265 and rs6295, combined

Summary

Introduction

The monoamine neurotransmitter serotonin has an essential role in behavior and cognition[1]. For affective disorders serotonin is regarded as the decisive neurotransmitter, implicated in the etiology and course of the most common neuropsychiatric diseases major depressive disorder (MDD) and anxiety disorders[2,3]. Even fundamental questions as whether reduced or increased 5-HT1A binding should be regarded as neuronal correlates of MDD have not been answered satisfactorily. More recent PET findings have provided some consistency for increased 5-HT1A binding in drug naïve MDD compared to healthy controls, but these results may be dependent on the imaging methodology and specific regions analyzed[8,9,10,11,12].

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