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.