Interaction between 5-HTTLPR and 5-HT1B genotype status enhances cerebral 5-HT1A receptor binding

Baldinger, P.; Kraus, Christoph; Rami‐Mark, Christina; Gryglewski, Gregor; Kranz, Georg S.; Haeusler, Daniela; Hahn, Andreas; Spies, Marie; Wadsak, Wolfgang; Mitterhauser, Markus; Rujescu, Dan; Kasper, Siegfried

doi:10.1016/j.neuroimage.2015.01.049

Cited by 15 publications

(10 citation statements)

References 52 publications

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“…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.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Methodsmentioning

confidence: 99%

“…There is evidence for interaction effects of functional genetic variations of BDNF and other genes in the serotonergic system 41–43 . A recent review examining the 5-HT 1A receptor in depression suggested interaction between BDNF and HTR1A as an important target for future PET studies 32 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…33,35 In addition, other studies found that being homozygous for the L A allele was associated with increased serotonin transporter binding. 125,126 Since the serotonin transporter modulates the concentration of serotonin at the synaptic cleft, an increase in the transcription of the transporter would decrease the amount of serotonin at the synaptic cleft. In a number of studies, individuals who possessed one or two doses of the low activity alleles (S or L G ) were more likely to develop behavioral disorders (e.g., depression) when they experienced stressful life events.…”

Section: Discussionmentioning

confidence: 99%

Associations Between Neurotransmitter Genes and Fatigue and Energy Levels in Women After Breast Cancer Surgery

Eshragh

Dhruva

Paul

et al. 2017

Journal of Pain and Symptom Management

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Context Fatigue is a common problem in oncology patients. Less is known about decrements in energy levels and the mechanisms that underlie both fatigue and energy. Objectives In patients with breast cancer, variations in neurotransmitter genes between Lower and Higher Fatigue latent classes and between the Higher and Lower Energy latent classes were evaluated. Methods Patients completed assessments prior to and monthly for 6 months following surgery. Growth mixture modeling was used to identify distinct latent classes for fatigue severity and energy levels. Thirty candidate genes involved in various aspects of neurotransmission were evaluated. Results Eleven single nucleotide polymorphisms (SNPs) or haplotypes (i.e., ADRB2 rs1042718, BDNF rs6265, COMT rs9332377, CYP3A4 rs4646437, GALR1 rs949060, GCH1 rs3783642, NOS1 rs9658498, NOS1 rs2293052, NPY1R Haplotype A04, SLC6A2 rs17841327 and 5HTTLPR + rs25531 in SLC6A4) were associated with latent class membership for fatigue. Seven SNPs or haplotypes (i.e., NOS1 rs471871, SLC6A1 rs2675163, SLC6A1 Haplotype D01, SLC6A2 rs36027, SLC6A3 rs37022, SLC6A4 rs2020942, and TAC1 rs2072100) were associated with latent class membership for energy. Three of thirteen genes (i.e., NOS1, SLC6A2, SLC6A4) were associated with latent class membership for both fatigue and energy. Conclusions Molecular findings support the hypothesis that fatigue and energy are distinct, yet related symptoms. Results suggest that a large number of neurotransmitters play a role in the development and maintenance of fatigue and energy levels in breast cancer patients.

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“…between functional polymorphisms in genes within the serotonergic system and protein binding potential of proteins within the serotonin system as assessed by PET. For example, a recent study demonstrated an interaction effect of the 5-HTTLPR polymorphism in the SERT gene with a polymorphism at the rs6296 locus in the serotonin 1B receptor gene on 5-HT 1A BP ND measured by [ 11 C]WAY-100635 (Baldinger et al, 2015). As genotyping at these loci was available in this sample, we performed an exploratory analysis, examining relationships between genotype at these loci and [ 11 C](+)-McN-5652 or [ 11 C]WAY-100635 binding in the a priori ROIs in this study; no significant relationships were observed (all p>0.05, uncorrected for multiple comparisons).…”

Section: Discussionmentioning

confidence: 99%

Lack of association between the serotonin transporter and serotonin 1A receptor: an in vivo PET imaging study in healthy adults

Strupp-Levitsky¹,

Miller

Rubin‐Falcone

et al. 2016

Psychiatry Research: Neuroimaging

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The serotonin neurotransmitter system is modulated in part by the uptake of synaptically released serotonin (5-HT) by the serotonin transporter (5-HTT), and by specific serotonin autoreceptors such as the somatodendritic 5-HT1A receptor, which can limit serotonin neuron depolarization. However, little is known about how 5-HTT and 5-HT1A are related in vivo. To study this question, we reanalyzed positron emission tomography (PET) data obtained earlier in 40 healthy participants (21 females) using [11C]WAY-100635 for quantification of 5-HT1A binding and [11C](+)-McN-5652 for quantification of 5-HTT binding. We hypothesized negative correlations between 5-HT1A binding in the raphe nuclei (RN) and 5-HTT binding in RN terminal field regions. Controlling for sex, no significant correlations were found (all p>0.05). Similarly, an exploratory analysis correlating whole-brain voxel-wise 5-HTT binding with 5-HT1A binding in RN identified no significant clusters meeting our a priori statistical threshold. The lack of correlation between 5-HT1A and 5-HTT binding observed in the current study may be due to the different temporal responsiveness of regulatory processes controlling the somatodendritic 5-HT1A receptor and 5-HTT in response to changing availability of intrasynaptic serotonin.

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Interaction between 5-HTTLPR and 5-HT1B genotype status enhances cerebral 5-HT1A receptor binding

Cited by 15 publications

References 52 publications

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

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

Associations Between Neurotransmitter Genes and Fatigue and Energy Levels in Women After Breast Cancer Surgery

Lack of association between the serotonin transporter and serotonin 1A receptor: an in vivo PET imaging study in healthy adults

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