Influence and interaction of genetic polymorphisms in catecholamine neurotransmitter systems and early life stress on antidepressant drug response

Abstract

Catecholamine neurotransmission plays an important role in major depression. Variation in genes implicated in the synthesis and signal transduction of catecholamines (norepinephrine and dopamine) may interact with environmental factors to affect the outcome of antidepressant treatment. We aimed to determine how a range of polymorphisms in noradrenergic and dopaminergic genes influence this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. In a sample of 308 Chinese Han patients with major depressive disorder, 13 single nucleotide polymorphisms (SNPs) in coding regions of six genes (MAOA, SLC6A2, TH, COMT, DRD2, DRD3) with minor allele frequencies >5% were successfully genotyped from an initial series of 35 SNPs in 11 candidate genes associated with catecholamine neurotransmission. The responses to 6 weeks' treatment with antidepressant drugs was determined by changes in the 17-item Hamilton Depression Rating Scale (HAMD-17) score, and previous stressful events were evaluated by the Life Events Scale (LES) and Childhood Trauma Questionnaire-Short Form (CTQ-SF). Single SNP and haplotype associations with treatment response were analysed by UNPHASED 3.0.13, gene-gene interactions were analysed by generalized multifactor dimensionality reduction (GMDR) and gene-environment interactions by logistic regression. A haplotype in MAOA (rs1137070 and rs6323) was significantly associated with antidepressant response in the total group, the nonSSRI subgroup and the female subgroup. Two haplotypes in COMT (involving rs4633, rs4818 and rs769224) were significantly associated with antidepressant response in the nonSSRI subgroup. The SLC6A2 SNPs interacted with childhood trauma to influence antidepressant response. A haplotype in MAOA and two haplotypes in COMT are found to be associated with antidepressant treatment response in this sample. Stressors in early life may interact with polymorphisms in SLC6A2 to influence response to antidepressant treatment.