Genetic contributions to brain serotonin transporter levels in healthy adults
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The serotonin transporter (5-HTT) critically shapes serotonin neurotransmission by regulating extracellular brain serotonin levels; it remains unclear to what extent 5-HTT levels in the human brain are genetically determined. Here we applied [11C]DASB positron emission tomography to image brain 5-HTT levels and evaluated associations with five common serotonin-related genetic variants that might indirectly regulate 5-HTT levels (BDNF rs6265, SLC6A4 5-HTTLPR, HTR1A rs6295, HTR2A rs7333412, and MAOA rs1137070) in 140 healthy volunteers. In addition, we explored whether these variants could predict in vivo 5-HTT levels using a five-fold cross-validation random forest framework. MAOA rs1137070 T-carriers showed significantly higher brain 5-HTT levels compared to C-homozygotes (2–11% across caudate, putamen, midbrain, thalamus, hippocampus, amygdala and neocortex). We did not observe significant associations for the HTR1A rs6295 and HTR2A rs7333412 genotypes. Our previously observed lower subcortical 5-HTT availability for rs6265 met-carriers remained in the presence of these additional variants. Despite this significant association, our prediction models showed that genotype moderately improved prediction of 5-HTT in caudate, but effects were not statistically significant after adjustment for multiple comparisons. Our observations provide additional evidence that serotonin-related genetic variants modulate adult human brain serotonin neurotransmission.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 16426 |
| Tidsskrift | Scientific Reports |
| Vol/bind | 13 |
| Udgave nummer | 1 |
| Antal sider | 11 |
| ISSN | 2045-2322 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This study was supported by the Lundbeck Foundation and the Danish National Research Council, which funded the Center for Integrated Molecular Brain Imaging (10.1016/j.neuroimage.2015.04.025), the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 953327 (Serotonin & Beyond), the Research Council of Rigshospitalet (Grant ID A6594), the Augustinusfonden (Grant ID 19‐0489) and the Lundbeck Foundation (Grant R279-2018-1145: BrainDrugs). We acknowledge the John and Birthe Meyer Foundation for donating the PET scanner and the Cyclotron. We thank G. Thomsen, B. Dall, L. Freyr, S. V. Larsen and A. Dyssegaard for their help with the data collection with both the PET and MR scanners.
Funding Information:
This study was supported by the Lundbeck Foundation and the Danish National Research Council, which funded the Center for Integrated Molecular Brain Imaging (10.1016/j.neuroimage.2015.04.025), the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 953327 (Serotonin & Beyond), the Research Council of Rigshospitalet (Grant ID A6594), the Augustinusfonden (Grant ID 19‐0489) and the Lundbeck Foundation (Grant R279-2018-1145: BrainDrugs). We acknowledge the John and Birthe Meyer Foundation for donating the PET scanner and the Cyclotron. We thank G. Thomsen, B. Dall, L. Freyr, S. V. Larsen and A. Dyssegaard for their help with the data collection with both the PET and MR scanners.
Publisher Copyright:
© 2023, Springer Nature Limited.
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