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Psychosomatic Medicine 69:614-620 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

The Long and the Short of It: Associations Between 5-HTT Genotypes and Coping With Stress

Kay Wilhelm, MD, Jennifer E. Siegel, GRAD DIP Sc (Psych), Adam W. Finch, GRAD DIP Sc (Psych), Dusan Hadzi-Pavlovic, BSc, MPsychology, Philip B. Mitchell, MD, Gordon Parker, MD, PhD, DSc and Peter R. Schofield, DSc, PhD

From the School of Psychiatry (K.W., J.E.S., A.W.F., D.H.-P., P.B.M., G.P.), University of New South Wales and Black Dog Institute, Sydney, Australia; Garvan Institute of Medical Research (P.R.S.), Sydney; University of New South Wales, Sydney; and Prince of Wales Medical Research Institute, Sydney, Australia.

Address correspondence and reprint requests to Kay Wilhelm, Level 4 De Lacey Building, St Vincent's Hospital, Darlinghurst, NSW, Australia, 2032. E-mail: kwilhelm{at}stvincents.com.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: To examine whether the strategies people use to cope with stress were associated with differing serotonin transporter (5-HTT) genotypes. The short (s) variant of the 5-HTT promoter polymorphism has been associated with an increased likelihood of depression after significant life stress and greater emotional reactivity to fear-invoking stimuli.

Methods: Coping strategies were assessed within a longitudinal study in 1993. Ten years later, genomic DNA was obtained for 127 participants and genotypes for the 5-HTT promoter polymorphism were determined. Coping strategies were grouped into coping scales and also using an exploratory factor analysis. Using ordinal regression, associations were then examined between the coping scales and the 5-HTT genotype and gender.

Results: The short variant of the 5-HTT promoter polymorphism was associated with the use of fewer problem-solving strategies. This genotype effect differed significantly between the sexes and was greatest for males.

Conclusions: Our results indicate that coping is influenced by 5-HTT genotype, gender, and their interaction. We raise the possibility that a gene-related disposition to greater emotional reactivity may preclude those with the short variant of the 5-HTT promoter polymorphism from drawing on problem-solving strategies to deal with stress.

Key Words: serotonin transporter gene • 5-HTT • genotype • promoter polymorphism • coping • depression

Abbreviations: 5-HTT = serotonin transporter; SCL6A4 = serotonin transporter gene; MD = major depression; ABM = antidepressive behavior measure; CUS = coping under stress.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
The serotonin transporter (5-HTT) regulates serotonergic neurotransmission, which is central to many physiologic functions, including appetite, sleep, cognition, mood, and emotions. Transporter functioning is moderated by a polymorphism in the 5-HTT promoter region of the serotonin transporter gene (SCL6A4). In cell lines, the short (s) variant (allele) of the 5-HTT genotype reduces transcriptional efficiency of the 5-HTT gene promoter, resulting in reduced 5-HTT expression and serotonin uptake compared with the long (l) allele (1). Although an individual's 5-HTT genotype is fixed, it is possible that the regulatory effects imparted on 5-HTT functioning change over time, with genotype differences most evident during development (2,3).

Several recent studies have demonstrated an association between the 5-HTT promoter polymorphism, exposure to a series of adverse life events, and depression onset (2,4–8). Those with the short allele (denoted "s" carriers) exhibit a heightened vulnerability to adverse life events, leading to increased rates of onset of major depression (MD) (2). Furthermore, neuroimaging studies by Harriri and colleagues (9–11) and others (12) have revealed that "s" carriers respond to fearful stimuli with heightened activity in the amygdala, a brain region implicated in the regulation of emotions such as anxiety and fear.

Stress Response and Coping
There are two distinct, but interdependent, stress response processes that influence our risk to depression. Automatic processes are involuntary cognitive, emotional, and physiological reactions to a stressor, whereas coping strategies are attempts (both cognitive and behavioral) to diminish the physical, emotional, and psychological burden of an event (13).

Coping strategies can be conceptualized as "problem focused," if directed at controlling or changing the problem causing the distress, or "emotion focused," if directed toward managing internal emotional responses to the stressor (14). Whereas problem-focused coping responses are typically seen as a set of problem-solving behaviors (e.g., seeking information, making an action plan), emotion-focused coping strategies cover a range of conceptually distinct sets of behaviors. These are aimed at direct modulation of emotional reactions (e.g., think about the problem in a different light), distraction from the event and the associated distress (e.g., watch TV), engaging emotional support (e.g., seeking sympathy) or emotional release (e.g., breaking something).

Broadly speaking, problem-focused coping has been associated with good psychological adjustment and emotion-focused coping has been associated with poorer adjustment to stressful events (15–17). However, the adaptive utility of coping strategies is likely to depend on the nature of the stressor and factors related to the individual experiencing the event (13,18). Problem-focused strategies are thought to be more adaptive when the stressor is viewed as changeable, whereas emotion-focused strategies may be more helpful when the stressor is unchangeable (19,20). Gender differences on the use of coping strategies and their efficacy have also been reported, with women utilizing more emotion-focused strategies (21–23) and deriving greater benefit from them (24) than men who are more inclined to use problem-solving strategies or avoidance-oriented coping strategies (21,22).

Coping and a Genetic Vulnerability to Stress
Figure 1 illustrates the hypothesized pathways between 5-HTT genotype, stress responses (automatic and coping processes), and subsequent depression risk. We suggest that a hyperreactive automatic stress response among "s" carriers (as observed in neuroimaging studies (9,10) increases depression vulnerability in two ways: directly, via pathway "a," and indirectly (pathway "b") whereby coping responses mediate the relationship between the automatic stress response and depression risk. Here, high arousal has been associated with avoidance (emotion-focused) coping and lower arousal with approach-oriented (problem-focused) coping (25).


Figure 14
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  		Figure 1. Two hypothetical coping models demonstrating (A) the mediating role of coping in the relationship between 5-HTT genotype under exposure to stress and depression, and (B) the relationships between the variables measured in the present study of genotype, gender, and coping. 5-HTT = serotonin transporter.

 

Previously, we replicated Caspi's findings of a vulnerability associated with the short allele to developing depression after life stress within our study cohort (4). In this paper, we explore pathway "b"—whether the 5-HTT genotype is associated with the use of different coping responses under stress and whether gender influences this relationship. We anticipated that "s" carriers would have developed a greater use of coping strategies intended to lower emotional arousal given their heightened reactivity to stress.


   METHOD
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Procedure and Materials
In 1978, students completing a 1-year postgraduate teacher training program were invited to participate in a longitudinal study to examine likely psychosocial risk factors contributing to the anticipated evolution of gender difference in rates of depression and anxiety disorders. This cohort was selected as the members were of similar age and had equal career and life opportunities, which helped to minimize the range of possible psychosocial confounders. The 170 students (114 women and 56 men; mean age = 23 years) who gave informed consent formed the study cohort and have been followed up at 5-year intervals (26–28). The participants were primarily Caucasian from European backgrounds (97%) with a small number of participants being from Chinese (n = 3) and Indian (n = 2) descent.

In 1993, participants remaining in the study completed a coping questionnaire, on which they indicated whether they used each of 48 stated behaviors "when stressed." Coping items were taken from the "Antidepressive Behavior Measure" (ABM) (29); an additional 27 items, relating to emotional expression (particularly irritability and anger) and action-oriented behaviors pertinent to depression, were drawn from the interview schedule for the Mood Disorders Unit (30) (Table 1). These additional coping strategies were chosen because they increased the breadth of the questionnaire and many were similar to those raised by participants during previous assessments. Table 2 describes the ABM scales and development of the new "Coping Under Stress" (CUS) scales derived from the larger item pool.


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  		TABLE 1. Development of the Coping Scales

 

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  		TABLE 2. Coping Dimensions Derived From Factor Analysis With Item Loadings for the 156 Cohort Members

 

Genetic Sampling
In 2003, we determined genotypes for the 5-HTT promoter polymorphism for this cohort (4). Of the 156 who had completed the coping questionnaire in 1993, 127 gave informed consent to genetic sampling. One hundred sixteen (91%) participants provided blood samples and 11 (9%) provided buccal swabs.

The following procedure was used to determine participants' 5-HTT promoter genotype (s/s, s/l or l/l) (4). Genomic DNA was extracted from whole blood using a standard salting out method (33). From cheek swabs, buccal cells were pelleted by centrifugation and digested overnight at 42°C in a 420-µl volume containing 1 µg/ml Proteinase K, 6 mmol/L Tris-Cl pH 7.5, 6 mmol/L ethylenediamine tetraacetic acid (EDTA), 3% Na sarkosyl, 1.2 M GuHCl, and 0.5 M ammonium acetate. DNA was purified from the digest by standard chloroform extraction and ethyl alcohol (ETOH) precipitation, and resuspended in dH2O. The 5-HTT gene-linked promoter region was amplified with the following primers: forward 5'-TGCCGCTCTGAATGCCAGCAC-3', and reverse 5'-GCGGGATTCTGGTGCCACCTA-3', to generate a 464bp product for the 16 repeat (l) allele, and 420bp for the 14 repeat (s) allele. PCR was carried out in 25-µl volumes containing 1x Optiprime mastermix (Stratagene); 1x Optibuffer I (Stratagene), 400 mmol/L Betaine, 160 µM deaza dNTPs; 20 ng template DNA; 20 pmole each primer, and 1 U AmpliTaq Gold DNA polymerase (Applied Biosystems, Carlsbad, CA). Reactions were cycled with initial denaturation at 94°C for 12 minutes, followed by 35 cycles of 94°C for 30 seconds, 65°C for 45 seconds, 72°C for 1 minute, and a final extension of 10 minutes at 72°C. Products were visualized under UV light following electrophoresis in 2% agarose gels.

Statistical Analyses
Factor analysis was performed using MPLUS (34) and ordinal regression was performed using the LOGISTIC procedure in SAS (v. 9) (35). All other statistical procedures were conducted using SPSS for Windows (v. 13) (36).

Coping scale scores were computed from a count of the endorsed coping items. Data for the coping variables did not consistently meet the assumptions of normality nor did they fit distributions for count data. The coping data were thus treated as ordinal data and the appropriate nonparametric tests were used (i.e., Mann-Whitney U test and ordinal regression).

For the dimensions noted in Table 1, the Kruder-Richardson 20 alpha for internal consistency was 0.64 for Problem Solving, 0.57 for Emotional Regulation, 0.63 for Distraction, and 0.72 for the Anger/Tension Release scale. Although modest based on conventional criteria (37), these values are comparable to those reported for previous measures (23). Previous research has shown that increases in problem-solving behavior were associated with reduced drinking behavior (38).

A series of ordinal regression analyses was conducted, using the cumulative logit model, to examine the impact of the 5-HTT genotype, gender and the gender by genotype interaction on each of the ABM and CUS coping scales. The short allele has been observed to be functionally dominant in terms of 5-HTT expression and serotonin uptake (2) and amygdala hyperreactivity (11). For these reasons, participants with one or two short alleles (s/s and s/l genotypes) were combined into a single group ("s" carriers) and compared with the l/l homozygotes for all regressions.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
A total of 156 participants completed the coping inventory in 1993 (age = 38.2 ± 4.2 years, mean ± standard deviation (SD)), including 104 women. In 2003, the mean for those who provided genetic material (n = 128) was 47.6 ± 2.7 years; there were 85 women. Genotype frequencies (s/s, n = 27, 20%; s/l, n = 63, 49%; and l/l, n = 37, 30%) were in Hardy-Weinberg equilibrium ({chi}2 < 0.01 (2), p = .99). There were no significant gender differences in genotype frequencies ({chi}2 = 4.78 (2), p = .09) and frequencies for males (s/s, n = 10, 23%; s/l, n = 25, 58%; and l/l, n = 8, 19%; {chi}2 = 1.18 (2), p = .55) and females (s/s, n = 17, 20%; s/l, n = 38, 45%; and l/l, n = 30, 35%; {chi}2 = 0.61 (2), p = .74) were in Hardy-Weinberg equilibrium. When genotype groups were dichotomized by presence or absence of a short allele, the gender difference in genotype distribution reached significance ({chi}2 = 3.81 (1), p = .05), with more male "s" carriers than expected.

There were no significant differences between the groups who did and did not provide genetic material on gender (33% versus 35% female, {chi}2 = 0.02 (1), p = .89) nor the total number of coping strategies they reported having used (15.3 ± 6.5 versus 14.7 ± 5.8; z = –0.44; p = .66). Nonproviders were older (50.5 ± 7.5 years) than providers of genetic material (47.6 ± 2.7 years); t(29.3) = 2.0; p = .06. This difference can be largely attributed to the higher rates of study drop out among older participants before gene sampling for reasons including ill health or death.

Those with one or two copies of the s allele (i.e., "s" carriers) reported using fewer coping strategies overall (n = 90; 14.6 ± 6.8) than those with the l/l genotype (n = 37; 16.8 ± 5.3), with this difference approaching significance (z = 1.73; p = .09). Females (16.7 ± 6.2) reported a wider range of coping strategies than males (12.1 ± 5.6), z = 4.20; p < .001.

Table 3 shows the mean and SD values of the count of coping strategies reportedly used for the ABM and the factor analytically derived CUS scales by 5-HTT genotype (s/s, s/l, l/l). The mean responses for the s/l genotype group were increasingly similar to that of the s/s group than the l/l group on the CUS Anger/Tension Release, ABM Socialization, and each of the problem-solving scales.


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  		TABLE 3. Means and Standard Deviations by 5-HTT Genotype on the ABM and CUS Coping Scales for 127 Cohort Members

 

Correlations between ABM and CUS scale scores ranged from –0.13, between CUS Problem Solving and Recklessness, to 0.88, between ABM Problem-Solving and CUS Problem-Solving, indicating a high degree of construct overlap between the two problem-solving scales. There were also strong associations between Distraction and Socialization (r = 0.75) and a moderate association between Anger/Tension Release and Recklessness (r = 0.46).

Ordinal Logistic Regression
Table 4 presents the ordinal logistic regression models testing main effects of the 5-HTT genotype and gender, and the genotype-gender interaction on each of three ABM and four CUS coping scales. The scale variables were recoded with some extreme categories (high or low counts) aggregated to ensure that the proportional odds assumption was upheld and there were adequate cell numbers for each ordinal regression. For example, those with scores of ≥3 on the 8-item CUS Emotional Regulation scale were aggregated, resulting in a four-category format (i.e., 0, 1, 2, 3). Using the same procedure, eight-category CUS Anger/Tension Release and Distraction scales, and a seven-category CUS Problem-Solving scale were formed. ABM Recklessness, Socialization, and Problem-Solving scales were recoded into three, four, and five categories, respectively.


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  		TABLE 4. Ordinal Regressions of the 5-HTT Genotype, Gender, and the Genotype-Gender Interaction on Each Coping Factor for 127 Cohort Members

 

As shown in Table 4, the "s" carriers reported utilizing significantly fewer problem-solving coping strategies on the ABM and CUS scales and there were no other significant associations between genotype and coping scales. On the CUS scales, women reported using significantly more anger/tension release strategies, although there was a trend (p = .06) for men to report using more problem-solving strategies. On the ABM scales, women reported using more socialization coping strategies and significantly fewer problem-solving strategies.

Significant gender-genotype interactions were found on both Problem Solving scales (Table 4). The "s" allele seemed to be associated with fewer problem-solving strategies for both genders, but this effect was much stronger for the men (as illustrated in Figure 2).


Figure 24
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  		Figure 2. Reported use of CUS problem-solving strategies by gender and 5-HTT genotype. CUS = coping under stress; 5-HTT = serotonin transporter.

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
We have previously shown that the short variant of the 5-HTT promoter polymorphism is associated with an increased vulnerability to developing depression after life stress in this cohort (4). We now report an association between the "s" allele and documented use of fewer problem-solving strategies when responding to stress. The present findings may assist in understanding the behavioral mechanisms responsible for the increased risk of developing depression post exposure to stressful events for "s" carriers (2).

Gender and Coping
Women reported using more coping strategies overall and significantly more emotion-focused strategies, including anger/tension release and socialization strategies, reflecting gender distributions reported elsewhere (21–24). The trend for men to report the use of more problem-solving strategies is also consistent with past findings (21,22).

Coping and 5-HTT Genotypes
The results did not support our hypothesis that "s" carriers would use more emotion-focused responses. Instead, we observed that "s" carriers reported using fewer problem-solving strategies.

Problem-focused coping has been reported to be effective in reducing stress and lowering vulnerability to depression (39,40). The use of problem-focused strategies is thought to diminish when people perceive a loss of control in stressful situations they encounter (41). In reconciling our findings, we speculate that "s" carriers perceive stressful situations as more overwhelming and uncontrollable than l/l homozygotes and are thus less likely to employ problem-focused coping.

The interaction observed between gender and 5-HTT genotype on problem-solving coping indicates a much stronger association between the "s" allele and the reported use of fewer problem-solving strategies for males than females. As previous research has reported that women tend to use more emotion-focused strategies and demonstrate improved outcomes when using these strategies (24), we speculate that women share a general preference for these emotion-focused strategies and tend to use them regardless of differences in automatic arousal associated with their 5-HTT genotype. In contrast, gene-related hyperreactivity to stressors among males may have a more noticeable inhibitive effect on their use of problem-solving coping responses, given their preference for (and reliance on) this form of coping (21,22).

The assessment of coping was conducted after the first MD onset for most cohort members who developed depression and few reported a depressive episode across the remaining follow-up interval. Thus, we were unable to assess the efficiency of the coping responses (and whether this differed by genotype) in terms of preventing first depression onset as well as any future MD episodes (whether first or recurrent). Additionally, mood state was not controlled for in this study and has been reported to affect coping (29); however, we note that were no differences in lifetime rates of MD by genotype (4).

Sample Characteristics and Genotype Distributions
The genetic and sociodemographic make-up of our study group raises issues that can be addressed via replication studies. Our sample was relatively homogeneous in terms of age, socioeconomic status, education, and ethnicity, thus limiting the generalizability of our findings. The observed associations between genotype and coping may have been influenced by gender differences in genotype distributions as well as population stratification. However, we note that genotype distributions were in Hardy-Weinberg equilibrium (for the total sample and within the sexes) and the sample was comprised almost entirely of Caucasians from European ancestry; hence, ethnic variation in the allelic frequency of the 5-HTT gene promoter (42) was unlikely to have biased our findings.

Coping Scales
The reliability and validity of the CUS measure requires further examination including that of its factor structure within other populations, stability over time, and cross validation against established measures of coping such as the COPE Inventory (43) or Ways Of Coping Questionnaire (44). Our sample was drawn from a very different population to the primary care patients recruited by Parker and Brown (29) and new coping items were added and the response format was modified; hence, substantial differences in the dimensional structures of the CUS and ABM were expected. The similarity of the ABM and CUS Problem-Solving scales therefore suggests a relatively stable, unitary construct.

Summary and Future Directions
This preliminary analysis employed a small, socially homogeneous sample and may not have detected some true associations between gender, genotype, and coping. Nevertheless, we found a significant gender-moderated difference in coping responses reported between the 5-HTT genotype groups. The inhibition of problem-solving via an exaggerated stress response represents a potential mechanism underlying the restricted range of problem-solving coping responses reported among "s" carriers. Replication of these findings, as well as the examination of the causal relationships between 5-HTT gene, coping with stress and depression occurrence, are needed. Further investigation of the genetic link to coping may potentially shed light on why some "at risk" individuals are resilient to the effects of adversity (45).

This study was granted approval by the University of New South Wales Human Research Ethics Committee. The authors thank Ian Blair and Anna Scimone for genetic analyses. We also give special thanks to the cohort members for their continuing interest and generous donation of their time and samples.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication March 12, 2006; revision received May 14, 2007.

This work is supported by NHMRC Grants 222708, 230802, and 157209 and by an Infrastructure Grant from the Centre for Mental Health, NSW Department of Health.

DOI:10.1097/PSY.0b013e31814cec64


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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