Research report
Working conditions, serotonin transporter gene polymorphism (5-HTTLPR) and anxiety disorders: A prospective cohort study

https://doi.org/10.1016/j.jad.2013.07.013Get rights and content

Abstract

Background

The etiology and pathology of anxiety disorders involve both genetic and environmental influences. Adverse working conditions may contribute to the development of anxiety. The serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in stress sensitivity. Therefore, we investigated the potential interplay between 5-HTTLPR and job-related risk factors in the prediction of the occurrence of anxiety.

Methods

We conducted a prospective study using the first two waves of a Swedish population-based cohort. At Wave I, 1585 individuals without anxiety, depression or dysthymia who were active in the labor market during both waves were included. Information on job demands, skill discretion, decision authority and social climate was collected at Wave I. After a three year interval, the presence of anxiety disorders was determined at Wave II. All 1585 participants were genotyped for 5-HTTLPR. Both additive and multiplicative models were considered in examining the potential interaction between 5-HTTLPR and adverse working conditions on the development of anxiety.

Results

Anxiety was associated with high job demands but not with 5-HTTLPR. An interaction was observed between 5-HTTLPR and high job demands among females. Individuals with 5-HTTLPR high expression genotype (LL) developed anxiety disorders more frequently when exposed to high job demands compared to ‘LS/SS’ carriers.

Limitations

A limited number of participants developed anxiety.

Conclusions

High job demands predict the development of anxiety. The 5-HTT polymorphism has a moderating effect on the relationship between high job demands and anxiety among females.

Introduction

Converging lines of evidence suggest that genetic and environmental influences play important roles in anxiety etiology and pathology (Arnold et al., 2004, Hettema et al., 2001). A potential relationship between occupational stress and mental disorders has drawn the attention of social epidemiologists ever since Karasek introduced the Job Demand-Control model (JDC) in the late 1970s (Karasek, 1979), which was later extended to include also social support (Job Demand-Control-Support model JDCS) (Johnson and Hall, 1988, Theorell, 2000). A recent meta-analysis concluded that there is a causal relationship between, on one hand, high psychological job demands, low decision latitude, low social support and, on the other hand, common mental disorders (Stansfeld and Candy, 2006). However, with regard to the relationship between JDCS model and specifically anxiety disorders, findings from the reported longitudinal studies are inconclusive. Andrea et al. found that high psychological job demands predisposed for anxiety two years later, while low control at work did not; high social support exerted a preventive effect for anxiety (Andrea et al., 2009). Plaisier et al. found no association for psychological demands and control at work to anxiety two years later (Plaisier et al., 2007). Wieclaw et al. indicated that high psychological job demands were negatively related to incidence of hospitalizations due to anxiety syndromes, whereas low control was positively linked to this outcome (Wieclaw et al., 2008). Griffin et al. identified that low job control was associated with anxiety six years later (Griffin et al., 2002).

The serotonin transporter gene (SLC6A4) which encodes the serotonin transporter (5-HTT) is one of the most widely investigated candidate genes linked to stress sensitivity, as it regulates serotonin signaling (Caspi et al., 2010). The promoter region of SLC6A4 harbors a 44 bp insertion/deletion polymorphism, denoted serotonin transporter linked polymorphic region (5-HTTLPR), with the long allele (L) being associated with an increased expression of 5-HTT mRNA (Collier et al., 1996, Heils et al., 1996). Compared to the long ‘L’ allele homozygotes, lymphoblasts and platelets from those homozygous or heterozygous for the short ‘S’ allele (the ‘S’ carriers) have approximately 40% lower 5-HTT expression (Greenberg et al., 1999, Lesch et al., 1996). In addition, the ‘S’ carriers had lower 5-HTT binding in dorsal raphe nuclei, containing the highest density of 5-HTT (Lesch et al., 1996, Little et al., 1998). Previous studies demonstrated that the ‘S’ allele of 5-HTTLPR is linked to increased stimulus-provoked amygdala reactivity (Kenna et al., 2012, Munafo et al., 2008) and anxiety-related personality traits (Kenna et al., 2012, Munafo et al., 2008, Schinka et al., 2004). Caspi et al. suggested that the 5-HTTLPR moderates the effect of negative life events on depression and suicidality; the ‘S’ allele carriers exhibited higher depression and suicidality rate compared to ‘L’ homozygotes (Caspi et al., 2003). This finding could be confirmed in meta-analysis only when stratifying for the type of stressors (Karg et al., 2011). Only a few studies have addressed the 5-HTT×environmental adversity interplay in anxiety disorders (Gunthert et al., 2007, Klauke et al., 2011, Laucht et al., 2009, Stein et al., 2008, Zavos et al., 2012). Two studies found that the ‘S’ variant modified the effect of current daily stress or previous childhood maltreatment on anxiety sensitivity (Gunthert et al., 2007, Stein et al., 2008). In contrast, Klauke et al. and Laucht et al. reported that ‘LL’ carriers with childhood maltreatment or family adversity displayed higher anxiety sensitivity and anxiety disorder rates, respectively (Klauke et al., 2011, Laucht et al., 2009); while Zavos et al. found no interaction between unspecified stressful life events and 5-HTTLRP on anxiety sensitivity (Zavos et al., 2012). With regard to psychosocial job characteristics, a cross-sectional study with small sample size indicated the absence of interaction between 5-HTTLPR and supervisor's support on depressed mood (Katsuyama et al., 2008).

To our knowledge, no longitudinal study has assessed if the interaction between 5-HTTLPR and psychosocial work factors predisposes to anxiety. In view of the accepted hypothesis that genetic susceptibility can moderate the effect of environmental influences on psychiatric disease pathogenesis (Caspi and Moffitt, 2006), the present study was aimed at elucidating: (a) the association between psychosocial job characteristics and anxiety disorders three years later; (b) if 5-HTTLPR is related to anxiety disorders, independently of adverse job exposures; (c) the potential interaction between 5-HTTLPR and job risk factors on anxiety disorders three years later.

Section snippets

Subjects and study design

We applied a prospective cohort study design. Subjects were selected from participants of the first two phases of the PART study, a population-based longitudinal research on mental health, work and relations with Wave I (W1) from 1998 to 2000 and Wave II (W2) from 2001 to 2003 (Hällström et al., 2002). A sample of 8613 (42.3% male) individuals from 19,742 randomly selected Swedish residents participated in both waves by filling out two almost identical questionnaires with a three year interval;

Results

Adults in the labor market, with no anxiety and/or depression and/or dysthymia diagnosis, were at baseline scored for exposure to psychosocial work factors, and three years later assessed for anxiety disorders. All the analyses, both descriptive and analytical, use one degree of freedom. In total, 1585 individuals were recruited into the current study, including 165 (10.4%) anxiety cases and 1420 (89.6%) that remained without anxiety and depression diagnosis (Table 1). Female gender, high job

Discussion

In an effort to elucidate whether 5-HTTLPR genotype modifies the effect of self-reported psychosocial work factors on anxiety disorders, we performed a prospective cohort study, and tested both additive and multiplicative interactions. To the best of our knowledge, this study is the first prospective risk model of the interaction between job-related risk factors and 5-HTTLPR on anxiety psychopathology.

We found an additive interaction between high psychological job demands and the 5-HTTLPR on

Role of funding source

This work is supported by Grants from Swedish Council for Work Life and Social Research (2007-1157) to IL, Swedish Research Council Medicine (2009-5546 and 2010-3631) to YF and CL respectively, Stockholm County Council (LS 0801-0019) to YF, and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet to YF and CL.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgments

None.

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