BackgroundDepression and related phenotypes, such as anxiety and neuroticism are thought to have a common genetic background. The malfunction of the serotonergic system is likely to play an important role in the etiology of these phenotypes, with compelling evidence coming from animal and human studies. However, recent studies indicate that other factors should be investigated, such as environmental stress. AimTo investigate the role of the serotonergic gene variants (HTR1A-7 and SLC6A4) in depression, anxiety and neuroticism, in interaction with each other and other factors, such as stressful events.MethodTwo large independent Caucasian cohorts, haplotype tagging single nucleotide polymorphisms (htSNPs) and existing genome-wide genotype data were used. Phenotypes were assessed by detailed questionnaires about psychiatric phenotypes (depression, anxiety and neuroticism) as well as background information, such as physical health. Environmental stress factors were investigated in one cohort by self-reported life event (recent and childhood) questionnaires. Healthy participants from this cohort took part in a computerised task to measure the effect of a functional polymorphism in the HTR1A gene on threat-related emotional information processing.ResultsMy study confirmed the importance of stressful life events in depression and anxiety modulated via the 5-HT1A and 5-HT1B autoreceptor, but not via the SLC6A4. I found evidence for epistatic interaction between HTR2A and SLC6A4 genes and between different subunits of the HTR3 gene which may contribute towards the depressive phenotype. Finally, certain alleles of SNPs in other serotonergic receptors (5-HT4 and 5-HT6) were also associated with depression, anxiety and neuroticism however, this association was weak. On the other hand, my study did not provide evidence for the interaction between the serotonin transporter 5-HTTLPR polymorphism and stressful life events which is widely reported in the literature.ConclusionThis study provides further support for the serotonergic hypothesis of depression and confirms the role of the environment in the aetiology of depression. The results show evidence of possible epistatic interaction between the SLC6A4 and HTR2A genes. These results highlight the complex interactions between the members of the serotonergic pathway as well as the role of the environment on the individual.