TY - JOUR
T1 - Epistasis of HTR1A and BDNF risk genes alters cortical 5-HT1A receptor binding
T2 - PET results link genotype to molecular phenotype in depression
AU - Kautzky, Alexander
AU - James, Gregory M.
AU - Philippe, Cecile
AU - Baldinger-Melich, Pia
AU - Kraus, Christoph
AU - Kranz, Georg S.
AU - Vanicek, Thomas
AU - Gryglewski, Gregor
AU - Hartmann, Annette M.
AU - Wadsak, Wolfgang
AU - Mitterhauser, Markus
AU - Rujescu, Dan
AU - Kasper, Siegfried
AU - Lanzenberger, Rupert
PY - 2019/12/1
Y1 - 2019/12/1
N2 -
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.
AB -
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.
UR - http://www.scopus.com/inward/record.url?scp=85060250945&partnerID=8YFLogxK
U2 - 10.1038/s41398-018-0308-2
DO - 10.1038/s41398-018-0308-2
M3 - Journal article
C2 - 30664620
AN - SCOPUS:85060250945
SN - 2158-3188
VL - 9
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 5
ER -