In this study, we used PET scans of 254 healthy participants and 90 patients with MDD to determine the relation between peripheral SLC6A4 and TPH2 methylation and two key features of the serotonergic brain signalling system, i.e. 5-HTT and 5-HT4, imaged with combined with [11C]DASB and [11C]SB207145 PET radiotracers, respectively. This evidence concerns the gene SLC6A4 and major depressive disorder.