New Evidence for the Association of the Serotonin Transporter Gene (SLC6A4) Haplotypes, Threatening Life Events, and Depressive Phenotype

Background: Since the first report of the significant gene-environment interaction (G × E) in depression published by Caspi et al., the literature is considerably contradictory in this field. To clarify this question, we analyzed the interaction between the serotonin transporter gene (SLC6A4) and threatening life events (TLE) on Zung Self-Rating Depression Score (ZSDS). Methods: Five markers tagging the whole SLC6A4 gene (5-HTTLPR and 4 single nucleotide polymorphisms: rs2020942, rs140700, rs3798908, rs1042173) were genotyped in 567 nonclinical individuals. Generalized linear models were used to analyze single marker associations, and likelihood ratio tests and score tests were used for haplotype analysis. Results: Haplotype analysis revealed a significant global effect of haplotypes on ZSDS score in high TLE subgroup (p = .008). Besides the 5-HTTLPR, rs140700 tagging the middle region of the gene had significant effects. Subjects carrying the A allele of rs140700 scored lower on ZSDS independently of 5-HTTLPR carrier status. Explained variances for depressive phenotype were 1%, 4%, and 6% when 5-HTTLPR, 5-HTTLPR × TLE and 5-HTTLPR × rs140700 × TLE were included in the model, respectively. Conclusions: Our results demonstrate heterogeneity of individuals carrying S alleles of 5-HTTLPR in association with high TLE providing possible explanation for the inconsistency of previous studies. In addition to the promoter, the middle region of the SLC6A4 gene carries the G × G × E interaction for mood, and this new model provided a higher explained variance. We report the first evidence for the significant effects of haplotypes of the SLC6A4 gene and threatening life events on depressive phenotype. © 2008 Society of Biological Psychiatry.