Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Sci Rep. 2023 Sep 30;13(1):16426. doi: 10.1038/s41598-023-43690-x.
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 [C]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.
血清素转运体（5-HTT）通过调节脑外的血清素水平来严重影响血清素神经传递；目前尚不清楚人类大脑中的 5-HTT 水平在多大程度上是由遗传决定的。在这里，我们应用 [C]DASB 正电子发射断层扫描来描绘大脑中的 5-HTT 水平，并评估与五个常见的与血清素相关的遗传变异的关联，这些变异可能间接调节 5-HTT 水平（BDNF rs6265、SLC6A4 5-HTTLPR、HTR1A rs6295、HTR2A rs7333412 和 MAOA rs1137070）在 140 名健康志愿者中。此外，我们还使用五重交叉验证随机森林框架探索了这些变体是否可以预测体内 5-HTT 水平。MAOA rs1137070 T-携带者的大脑 5-HTT 水平明显高于 C-纯合子（尾状核、壳核、中脑、丘脑、海马、杏仁核和新皮层的 2-11%）。我们没有观察到 HTR1A rs6295 和 HTR2A rs7333412 基因型的显著关联。我们之前观察到 rs6265 met-携带者的皮质下 5-HTT 可用性较低，在存在这些额外变体的情况下仍然存在。尽管存在这种显著的关联，但我们的预测模型表明，基因型在尾状核中适度改善了对 5-HTT 的预测，但在进行多重比较调整后，效果并不具有统计学意义。我们的观察结果提供了额外的证据，表明与血清素相关的遗传变异调节成年人大脑的血清素神经传递。
