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Psychosomatic Medicine 69:391-395 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

Genetic Variants in the DRD2 Gene Moderate the Relationship Between Stressful Life Events and Depressive Symptoms in Adults: Cardiovascular Risk in Young Finns Study

Marko Elovainio, PhD, Markus Jokela, MSc, Mika Kivimäki, PhD, Laura Pulkki-Råback, PhD, Terho Lehtimäki, MD, PhD, Nina Airla, MSc and Liisa Keltikangas-Järvinen, PhD

From the Department of Psychology (M.E., M.J., M.K., L.P.-R., L.K.-J.), University of Helsinki, Helsinki, Finland; National Research and Development Center for Welfare and Health (M.E.), Helsinki, Finland; Department of Epidemiology and Public Health (M.E., M.K.), University College London, London, UK; Department of Clinical Chemistry (T.L., N.A.), Tampere University Hospital, Tampere, Finland; Medical School (T.L., N.A.), University of Tampere, Tampere, Finland.

Address correspondence and reprint requests to Liisa Keltikangas-Järvinen. Department of Psychology, P.O. Box 9, FIN-00014, University of Helsinki, Helsinki, Finland. E-mail: Liisa.keltikangas-jarvinen{at}helsinki.fi


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: To examine the potential moderating role of DRD2 polymorphism (rs1800497) in the association between stressful life events and depressive symptoms among young adults. Although stressful life events, such as divorce, unemployment, and serious illness in the family, are generally associated with negative health outcomes, including depressive symptoms, there are large individual differences in coping with such events. A number of studies suggest that variants in dopamine receptor genes, such as DRD2, are associated with depression but it is unclear if such variants also modify the association between life events and depression.

Methods: We analyzed the prospective data on life events and depressive symptoms in 1992 and 2001 related to 1611 young adults (672 men and 939 women, aged 15–30 years at baseline) who participated in the ongoing population-based cardiovascular risk in young Finns study.

Results: Occurrence of stressful life events was associated with increased risk of subsequent depressive symptoms in men and women. However, this association was seen only among those who carried A2/A2 (n = 872) genotype. No such association was detected in participants carrying A1/A1 or A1/A2 (n = 486) genotype.

Conclusion: DRD2 polymorphism moderates the effect of stressful life events on depressive symptoms and those who carry A2/A2 DRD2 genotypes may be more vulnerable than others.

Key Words: genetic • DRD2 • life events • psychosocial • depression

Abbreviations: BMI = body mass index; CHD = coronary heart disease; CRYF = cardiovascular risk in young Finns; CVD = cardiovascular disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
A large body of research suggests that there is a link between stressful life events and later health problems (1–7). Stressful life events are also a potential source of psychological problems. For example, the number of life events, in general, and of specific events categorized as dangers, in particular, has been associated with the onset of anxiety (1), and a variety of different stressful events have been associated with an increased likelihood of depressive symptoms and mental distress (3). Major or cumulative life events have also demonstrated a relationship with health-risk behaviors, such as smoking and alcohol abuse (8). Divorce, being a victim of a crime, and decrease in financial position have been associated with increased prevalence of heavy drinking in men (9) but the evidence is not consistent for other event categories or life events in general (10).

Despite the extensive evidence on the association between life events and health, considerable individual differences in coping with such events have been reported (11). It has been suggested that there are dispositions, such as high optimism, that may protect against the adverse effects of stressful life event but the evidence so far has been mixed and based on self-reported data on both life events and the moderating factor.

The human central dopamingeric system and especially dopamine receptors are widely considered to play an important role in the development of depression, bipolar disorders, and depressive symptoms. Dopamine system has been shown to be involved in determining reactions to environmental stress (12) and some of dopamine reuptake inhibitors show antidepressant effects (13).

A genetic contribution to the etiology of depression has been well established, and the search for specific genetic loci is now underway (14,15). A number of studies have analyzed dopamine receptor genes, including polymorphisms in DRD2, for associations with bipolar disorder and depression or depressive symptoms (16,17). Of special interest is the Taq1A (C32806T) polymorphism, a C to T substitution located in a noncoding region of the DRD2 locus, as this genetic variant has been suggested to affect dopamine receptor D2 availability in postmortem striatal samples (18–20). The A1 (T) allele has also been associated with low dopamine density and lower mean relative glucose metabolic rate in dopaminergic regions in the human brain (20).

The first molecular genetic demonstrations of gene-environment interactions in human behavior evaluated the interaction effect between DRD2 gene polymorphism affecting dopamine receptor availability and family environment (21,22). In a sample of adolescent boys, Berman and Noble (1997) showed that family stress correlated negatively with cognitive functioning in boys carrying the "minor" allele of the DRD2 but not in others. However, it is unclear whether DRD2 polymorphisms may moderate the association between life events and depressive symptoms.

In this study, we longitudinally investigated the potential moderating effect of DRD2 polymorphism between life events and depressive symptoms in early adulthood. We genotyped a population-based sample of men and women, aged 15 to 30 years at baseline, and followed up this group for 9 years to determine the magnitude of the association between life events and depressive symptoms for carriers of each DRD2 polymorphism. Although most of the studies on life events are based on the list of 16 negative life events derived from those used in earlier studies (23,24), we focused on specific categories of particularly stressful major life events: a) death of spouse or child, b) divorce, or c) unemployment. These life events have consistently predicted health problems across a large variety of populations (5,7,25–27). We took into account the effects of other known psychosocial risk factors for depressive symptoms, such as low socioeconomic position in childhood and adulthood and behavioral risks (body mass index, alcohol consumption, and smoking).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Study Subjects
Selection Procedure and Participants
The participants were derived from the ongoing population-based study of cardiovascular risk in young Finns (CRYF) (28). In this prospective, epidemiological study, a randomized sample of 3600 healthy Finnish children and adolescents in age cohorts of 3, 6, 9, 12, 15, and 18 years has been followed from 1980. During the sixth follow-up of the CRYF in 2001 (21 years after the baseline), 2229 participants were reexamined for adulthood depressive symptoms and DRD2. The sample with complete data consisted of 1636 individuals (683 men and 953 women) who were 3 to18 years of age at the baseline in 1980. Compared with the eligible population at the baseline, the participants in the present sample were more often women ({chi}2 = 110.24; df = 1; p < .001) but other baseline differences were small and not statistically significant. Participants gave written consent, and the study was approved by local ethics committees.

DNA Extraction and DRD2 C32806T (rs1800497) Genotyping
Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood leukocytes using a commercially available kit and BioRobot M48 Workstation according to the manufacturer's instructions (Qiagen Inc., Hilden, Germany). DRD2 C32806T (rs1800497) was genotyped by employing the 5'exonuclease assay and fluorogenic allele-specific TaqMan MBG probes (29) using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA). The nucleotide sequences of primers and probes used in the polymerase chain reaction (PCR) were deduced from published sequences deposited in the GenBank and synthesized in conjugation with Applied Biosystems. PCR reaction mixture consisted of genomic DNA, 1x Universal PCR Master Mix, 900 nM of each primer, and 200 nM of each probe. Amplification was performed using the TaqMan Universal Thermal Cycling Protocol. After PCR, end-point fluorescence intensity was measured and genotype calling was carried out by the allelic discrimination analysis module. As a quality control, random duplicates were run.

Measures
Socioeconomic Position
Parental educational level and their income were requested from both parents of all participants. Three categories of early socioeconomic position were used based on the family income quartiles in 1980: high (highest 25%), medium, and low (lowest 25%). Also, parental education and participants' own education were used. Both parental and participants' own education was categorized into three levels: academic (studying at or graduated from a university); secondary education but not academic (high school or vocational school as their highest education); and comprehensive school (those who had not passed a secondary education). Information on the parent with a higher educational level was used in the analyses.

Health Risk Behavior
The health risk behaviors measured were smoking status (nonsmoker versus current smoker), alcohol consumption (units/week), and body mass index (BMI).

Life Events
Death or serious illness of spouse or children, divorce, and unemployment that occurred from 1992 to 2001 were determined by questionnaire surveys in 1992, 1997, and 2001. In the whole data, the frequencies of these categories were 21, 23, 220, and 1110, which are comparable distributions shown by other Finnish databases. The participants were divided into two groups: those who had experienced any of these event categories and others.

Depressive Symptoms
Depressive symptoms were assessed using a revised version of Beck's Depression Inventory (BDI) (30–32) In the present study, the subjects were asked to rate 21 items (e.g., "I often feel sad") on a 5-point scale ranging from totally disagree (1 point) to totally agree (5 points).

Other measurements included age and gender.

Statistical Analysis
Group differences in the distribution of the DRD2 polymorphism (any A1 genotype versus A2/A2 genotype) and the interaction analyses were analyzed using the analysis of variance and linear multivariate regression analysis. Any A1 genotype group was formed due to the small number of A1/A1 genotypes. Previous studies investigating the effect of DRD2 on various outcomes (depressive symptoms/alcohol consumption) have used similar genotype categories for the same reasons or just compared A2 and A1 alleles (33). Statistical significance was set at p ≤ .05. All regression models were adjusted for age. Statistical analysis was performed using the SAS software (Version 9.1).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
The genotype distributions in men and women followed the Hardy-Weinberg equilibrium (p > .25 and p> .17, respectively). Genotype frequencies were (A2/A2) 357 and (A1/A2 + A1/A1) 205 for men and (A2/A2) 515 and (A1/A2 + A1/A1) 281 for women. There was no significant difference between men and women in the overall genotype distribution ({chi}2 = 0.19; p = .66), family income ({chi}2 = 0.96; p = .61), participants' own education ({chi}2 = 0.97; p = .97), or parental education ({chi}2 = 5.81; p = .06). Women had significantly higher level of depressive symptoms in 1992 (t(1266) = 5.51; p > .001) and in 2001 (t(1609) = 5.67; p < .001) compared with men. Women had experienced life events slightly more often than men ({chi}2 = 4.71; p = .030). Men had higher BMI (t(1514) = –6.78; p < .001), smoked more often ({chi}2 = 10.64; p < .01), and consumed more alcohol (t(1266) = 15.67; p < .001) than women (Table 1).


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  		TABLE 1. Sample Characteristics

 

There were no statistically significant interaction effects between gender and life events on depressive symptoms in 1992 (F(4,1267) = 0.58; p = .45) or in 2001 (F(4,1610) = 0.00; p = .97). Thus, the regression analyses were conducted for men and women in combination. Of the potential confounding variables, such as parental education, family income, education, BMI, smoking, and alcohol consumption, only BMI was related to depressive symptoms in adulthood (p < .001) after adjustments for age, gender, and baseline (1992) depressive symptoms. Occurrence of life events was associated with increased adulthood depressive symptoms when adjusted for age, gender, and baseline depressive symptoms (p = .01). There was no significant association between DRD2 polymorphism and depressive symptoms (Table 2).


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  		TABLE 2. Standardized ß Coefficients From Linear Models for Depressive Symptoms in 2001 and Early and Adulthood Risk Factors in Men and Women Adjusted for Age, Gender, and Previous (1992) Depressive Symptoms

 

The interaction effect between DRD2 polymorphism and life events on depressive symptoms in 2001 was statistically significant (F(4,1610) = 4.84; p = .03) and this effect was robust to adjustments for the covariates (Table 3). The age, gender, and baseline-adjusted association between life events and depressive symptoms in 2001 was significant only in those who carried the A2/A2 genotype (ß = 0.11; p < .01). This association was robust to adjustment for any of the confounding factors. In the A1/A2 + A1/A1 genotype group, the association was weaker and statistically nonsignificant (ß = 0.03; p = .56) (Table 4). The mean values of depressive symptoms among those with and without life events according to DRD2 genotype are presented in Figure 1.


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  		TABLE 3. Interaction Effect of DRD2 and Life Events on Depressive Symptoms in 2001 (Standardized ß Coefficients, n = 1225)

 

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  		TABLE 4. Multiple Linear Regression Analyses for Depressive Symptoms in 2001 and Life Events in DRD2 Genotype Groups

 

Figure 11
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  		Figure 1. Depressive symptoms among those with and without life events according to DRD2 genotype.

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
We found a weak overall association of experiencing life events, such as serious illness or death in the family, divorce, or unemployment, and subsequent higher depressive symptoms among young adults. However, this association masked a gene-environment interaction by Taq1A (C32806T, SNP rs1800497) polymorphism in DRD2 gene with a stronger association among those who carried the A2/A2 genotype and a weaker association among other genotypes. The results of this study are in line with the previous ones, suggesting that experiencing stressful life events affects later depression. Our results also suggest that there are genetic factors that intensify or protect from later depressive symptoms among those exposed to stressful environmental conditions. More specifically, we found that variants in genes regulating the D2 dopamine receptors may modify the impact of life events on depressive symptoms.

Our results are in line with the previous results, suggesting a role of the DRD2 in the development of depressive symptoms. For example, Berman and colleagues (33) found that those boys of alcoholics carrying the A2/A2 genotype scored higher on BDI than those carrying any A1 genotype. According to the results of Lawford and co-workers (34), those patients of posttraumatic disorders with DRD2 A1/A2 genotype compared with those with the A2/A2 genotype had higher depression scores at baseline but they showed a significantly greater improvement in social functioning after paroxetine treatment compare with those having the A2/A2 genotype.

Berman and Noble (21) showed that family stress correlated negatively with cognitive functioning in boys carrying the A1 allele of the DRD2, but not in others. In the same sample, Ozkaragoz and Noble (22) reported that the association between parental alcoholism and extraversion was moderated by the DRD2, such that living in an alcoholic home was associated with high extraversion among boys carrying the A1 allele of the DRD2, but not among those carrying the A2 allele. Extraversion has, in turn, been associated with low depressive symptoms (35). Similarly, it has been found that the A1 allele has been associated with temperament dimension novelty seeking (36) and lower risk of depressive symptoms (37). Madrid and others (38), in turn, found the association between experienced economic stress and alcoholism to be moderated by the DRD2 polymorphism, so that the association was stronger in those carrying the A1 alleles. All these findings are consistent with the gene-environment interactions observed in this study.

In previous studies, the A1 + allele and the A1/A1 + A1/A2 genotype have shown a small main effect on emotional disorders, especially in non-Caucasian samples (39). However, because of their diminished brain dopaminergic reward system (40), it has been suggested (33) that boys with the A1/A1 + A1/A2 genotype have lower tolerance for experiencing negative effect than boys with the A2/A2 genotype and, consequently, develop better coping mechanisms to maintain their emotional balance during stressful life events.

It should be noted that the variant of the DRD2 gene focused in this study has been shown to have functional significance, as subjects carrying the DRD2 A1 allele, compared with findings for those without this allele, have reduced brain D2 dopamine receptors (18,20). Both animal and human studies implicate the D2 dopamine receptor (DRD2) gene in the pathogenesis of anxiety and depression. However, evidence on the interaction effects between environmental factors and genetic vulnerability in explaining emotional disorders, such as depressive symptoms, is still scarce and the final conclusions are not yet drawn.

Comparable results to ours, however, have been found on the interaction effect of serotonin transporter genes and life events on severity of depression. According to the results of Zalsman and others (41), lower expressing alleles of 5 HTTLPR predicted greater severity of major depression with moderate-to-severe life events compared with the higher expressing allele.

In interpreting the present results, it is important to note some limitations. Although the design of the CRYF study is population-based, the sample was restricted to men and women aged 15 to 30 years at baseline. The measure of depressive symptoms used in this study was a revised version of the widely used BDI. The subjects were asked to rate on a 5-point scale the second mildest BDI statements, which were suggested to be the most effective ones for measuring depressive symptoms in the normal population (42,43). Thus, a study replicating our project and using standard response format would offer an interesting comparison to the present results and would help to define the clinical significance of our findings.

We conclude that, although it is possible that a single gene plays a major role in determining susceptibility, the majority of depressive disorder involves more complex genetic mechanisms, such as the interaction of multiple genes and environmental factors. Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of depressive disorder. Our results now suggest that DRD2 may be one of such candidate genes that acts as a vulnerability factor and at the same time interacts with risky environment.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication November 29, 2006; revision received March 7, 2007.

This study was financially supported by the Signe and Ane Gyllenberg's Foundation (L.K.-J.); Grants 209514 (L.K.-J.), 209518 (L.K.-J.), 111056 (L.K.-J.), and 117604 (M.K.) from the Academy of Finland; Emil Aaltonen Foundation (T.L.); and Tampere University Hospital Medical Fund (T.L.).

DOI:10.1097/psy.0b013e31806bf365


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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