Research report
The role of serotonergic genes and environmental stress on the development of depressive symptoms and neuroticism

https://doi.org/10.1016/j.jad.2012.03.047Get rights and content

Abstract

Background

Depression is considered to be the result of a complicated synergy between genetic and environmental factors. Several genes of the serotonergic neurotransmission have been related to depression phenotypes, however results are inconsistent, possibly due to the oversight of the role of environmental stress.

Methods

We examined gene–environment (GxE) interactions with serotonergic genes on depressive symptoms and neuroticism in a homogeneous population-based sample of 415 females. We chose several genetic variants within candidate genes (SLC6A4, TPH2, HTR1A) that have been previously found to provide some evidence of association with depression outcomes.

Results

Single marker analyses showed a significant GxE interaction with several TPH2 variants, including rs4570625, on depressive symptoms. Significant GxE interactions were also observed with TPH2 haplotypes. No reliable associations were observed with SLC6A4 and HTR1A genes. We did not find any robust evidence of a direct impact of serotonergic genes on depressive symptoms or neuroticism.

Limitations

Due to the high number of analyses conducted, results must be interpreted with caution.

Conclusions

The present study indicates an association between TPH2 and depressive symptoms that is conditional on prior experience of stressful life events. Further evidence is provided about the role of the environment in genetic vulnerability to depression.

Introduction

Depression is one of the leading causes of disability affecting 5–7% of the population annually, and approximately 16% over a lifetime (Kessler et al., 2003). It has a great impact on public health due to its effects on personal wellbeing, functioning and productivity (Ormel et al., 2008). Cumulative evidence from evolutionary theory, epidemiology and experimental research indicates that mental disorders such as depression are likely to be caused by a synergy of genetic and environmental factors (Uher, 2009). Personality characteristics also play a role; neuroticism is a trait often linked to increased depression risk and can affect the course and treatment response of the disorder (Klein et al., 2011). Both depression and neuroticism have often been considered as phenotypes in genetic psychiatric research. A direct contribution to such complex phenotypes by only one genetic variant seems highly unlikely (Hasler et al., 2004). Genome-wide studies also point toward a more complicated genetic architecture since candidate gene association analyses are poorly replicated (Bosker et al., 2011). Failure to detect reliable genetic contribution strengthens the proposition that environmental risk plays a – possibly equal – role in the aetiology of depression.

Gene–environment interaction (GxE) research provides a potential pathway of understanding how genetic differences influence the likelihood that exposure to environmental stress will result in psychopathology (Nugent et al., 2011). Most studies to date have mainly focused on GxE with a promoter polymorphism (5-HTTLPR) located on the serotonin transporter gene (SLC6A4). This gene received increased attention due to its role in altering serotonin transporter function and neurotransmission, which play a key role in the neuropsysiology of depression. Most studies failed to show a direct association of this polymorphism with depression (Lasky-Su et al., 2005, Levinson, 2006), however, there is strong evidence in favour of a GxE interaction according to a recent review (Uher and McGuffin, 2010) and meta-analysis (Karg et al., 2011). Studies on the association between the 5-HTTLPR and neuroticism have produced inconsistent results (Munafo et al., 2009), but most studies have not taken the moderating effects of environmental stress into account.

Expanding research shows that variations on other genes within the serotonergic system also play a role in depression vulnerability. The serotonergic system is a reasonable source of candidate genes for depression, since this system is the target of selective serotonin reuptake-inhibitor drugs that are used in the treatment of depression. Evidence for serotonergic abnormalities in depression lies within tryptophan depletion paradigms, antidepressant pharmacokinetics and brain-imaging techniques exploring serotonergic neurotransmission (Cowen, 2008 for a review). Furthermore, stress responses are also modulated by such neurotransmission (El Hage et al., 2009). Within the serotonergic genes being investigated, Tryptophan Hydroxylase 2 (TPH2) gene is a promising candidate, since it is the rate-limiting enzyme in the synthesis of serotonin. TPH2 messenger RNA is highly expressed in the raphe nuclei, the main locus of serotonin synthesis (Zill et al., 2007). The TPH2 gene is located at chromosome 12q15, comprises eleven exons and covers a region of 93.5 kb (Haghighi et al., 2008). This gene seems to play a significant role in emotion regulation (as shown by neuro-imaging and behavioral studies), and it is also related to suicide, depression status and treatment response (Waider et al., 2011 for a review). However, no associations with depression and response to treatment have also been reported (Garriock et al., 2005, Gizatullin et al., 2008, Illi et al., 2009, Mann et al., 2008, Serretti et al., 2011). Only one study to date has examined the association between TPH2 variants and neuroticism and found no association (Juhasz et al., 2010). Most reliable evidence of GxE interactions comes from animal studies showing that allelic variation of TPH2 function is modulated by life adversity leading to unfavorable outcomes that resemble emotional disorders (Waider et al., 2011). To date, there is no complete consensus with regard to the specific variants within TPH2 involved in the aetiology of emotional disorders and the response to their treatments (Serretti et al., 2011). However, a number of studies have focused on the rs4570625, a SNP located in the promoter region of TPH2, that plays a functional role in serotonergic cell culture (Chen et al., 2008). It has been related to panic disorder (Kim et al., 2009), obsessive-compulsive disorder (Mossner et al., 2006) and attention deficit/hyperactivity disorder (Walitza et al., 2005) as well as neurocognitive endophenotypes of depression (Canli et al., 2005, Brown et al., 2005). In addition, a GxE interaction was found in children aged 10–14 years old, where variation on this polymorphism (rs4570625) and belonging to one-parent families was related to affective problems (Nobile et al., 2009).

Another gene variant that regulates brain serotonin system through receptors highly dense in the limbic areas and throughout the central nervous system is the 5-HT1A receptor gene (HTR1A). The HTR1A gene is located on chromosome 5q11.2–q13 and is intronless (Kobilka et al., 1987). Wu and Comings (1999) identified the −1019C/G polymorphism (rs6295) a SNP in the promoter region of the HTR1A gene. A number of studies have examined the relationship between this polymorphism and depression outcomes and have shown mixed results. The GG genotype has been associated with major depression and suicide (Lemonde et al., 2003) as well as with neuroticism (Strobel et al., 2003). However, no associations have also been found, both with depression (Arias et al., 2002, Huang et al., 2004, Chipman et al., 2010) and neuroticism (Hettema et al., 2008) as outcomes. Mixed results have been found with regard to antidepressant treatment response (Lemonde et al., 2004, Serretti et al., 2004, Kato et al., 2009). Furthermore, no evidence for an association between HTR1A and stressful life events was found with depressive symptoms in a population sample (Chipman et al., 2010). Recently, Nyman et al., (2011) found that polymorphisms within TPH2 and SLC6A4 interacted with high early developmental risk to predict depressive symptoms in a large population-based sample.

Failures to find consistent results between the serotonergic genes and depression or neuroticism may be due to the moderating role of environmental stress. Only a few studies have examined GxE interactions with serotonergic genes, other than with the 5-HTTLPR, in humans. The aim of the present study was to investigate the association between several variants within genes of serotonergic neurotransmission, including the SLC6A4, TPH2, and HTR1A genes, and stressful life events on depressive symptoms and neuroticism. We chose candidate genes that have been previously found to provide some evidence of association with depression-related outcomes.

Section snippets

Participants

The sample in the present study was composed by 415 women, recruited from the general population of Xanthi and surrounding villages, an area in the northeastern part of Greece. A homogeneous group of only females was chosen in order to exclude effects caused by gender variation. Participants were eligible for inclusion if they were female, aged 18 or more and consent to participate to the study. Exclusion criteria were represented by a severe or unstable medical condition that could impair the

SNP association analysis

Gene and Gene–environment interactions on depressive symptoms and neuroticism.

Sociodemographic and clinical characteristics of the sample are presented in Table 1. Age and occupation status were significantly related to the outcome (depressive symptoms or neuroticism) and analyses were repeated including these covariates. Furthermore, total BDI scores and Neuroticism were highly correlated, r=0.63 p<0.001 and either factor was considered as a covariate in the model with the respective outcome.

Discussion

The present study investigated genetic and environmental influences on depression in a genetically homogeneous sample. We did not find any robust evidence of a direct impact of serotonergic genes on depressive symptoms. However, we observed one gene–environment interaction that survived correction for multiple testing with one variant on the TPH2 gene on depressive symptoms.

There is increasing evidence in support of the role of the TPH2 gene in influencing serotonergic function and thereby

Role of funding source

This study was funded by the grant INTERREG IIIA/PHARE CBC Greece Bulgaria: Actions taken for the mental health of women of mountainous Xanthi. The work of Niki Antypa is supported by the Rubicon Grant awarded by the Netherlands Organization of Scientific Research (NWO). The funding bodies had no involvement in the research.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

We would like to thank the Prefect of Xanthi, G. Pavlidis; the Health Director of the Prefecture of Xanthi, A. Nearchou; and S. Vitoratou from the University Mental Health Research Institute in Athens, Greece, for their valuable assistance. We also thank the participants for taking part in the study.

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