The relationship of tryptophan hydroxylase-2 methylation to early-life stress and its impact on short-term antidepressant treatment response

Introduction: The gene tryptophan hydroxylase 2 (TPH2) encodes the associated rate-limiting enzyme in the biosynthesis 5-HT (serotonin). Early life stress and adult variability in TPH2 can correspond with diminished response to antidepressants for patients with major depressive disorder (MDD). DNA methylation is an epigenetic mechanism mediating gene expression, often tempered by environmental factors. Here, we investigate the influence of TPH2 methylation combined with stress on response to antidepressants within the first two weeks of treatment initiation. Methods: 291 Han Chinese patients with major depressive disorder and 100 healthy controls comprised the study population. The Life Events Scale (LES) and the Childhood Trauma Questionnaire (CTQ) rated recent and early-life stress. The primary outcome equaled a reduction by >= 50% from the Hamilton Depression Rating Scale-17 (HAMD-17) after 2 weeks of treatment. The Illumina HiSeq platform assessed methylation status in 38 CpG sites located upstream and downstream of 11 TPH2 polymorphism sites. Results: In 291 patients and 100 healthy controls, 3 CpG sites predict antidepressant treatment response per sex (TPH2-7-142, p=0.012; TPH2-1-43, p=0.033; TPH2-5-203, p=0.036). High-level CTQ scores relate significantly to DNA hypomethylation at CpG-site TPH2-8-237 in males (false discovery rate [FDR]-corrected p=0.038). Additionally, the interaction of hypermethylation in two CpG sites and elevated early-life stress may reduce antidepressant response (TPH2-5-203, FDR corrected p=0.010; TPH2-10-60, FDR corrected p=0.001). Conclusions: Our study suggests that TPH2 methylation and its interaction with early-life stress may impair antidepressant response, suggesting that pharmaco-epigenetic studies could identify epigenetic biomarkers for antidepressant response.