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

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

Research output: Journal article publicationJournal articleAcademic researchpeer-review

2 Citations (Scopus)

Abstract

Alterations of the 5-HT 1A 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-HT 1A receptor. Here we investigated interaction effects of rs6295 and rs6265 on 5-HT 1A receptor binding. Forty-six healthy subjects were scanned with PET using the radioligand [carbonyl- 11 C]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 (BP ND ) 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-HT 1A receptor binding by an average of 17% (mean BP ND 3.56 ± 0.74 vs. 2.96 ± 0.88). Mixed model produced an interaction effect of ROI and genotype on BP ND 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-HT 1A receptor profile comparable to affective disorders as increased 5-HT 1A 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.

Original languageEnglish
Article number5
JournalTranslational Psychiatry
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

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