Background
Depressive symptoms are one of the major mental health problems worldwide and are the main contributor to the global burden of disease in young people [
1]. Adolescence represents a developmental transition period between childhood and adulthood, characterized by marked changes in biological systems and physical maturation of the body and brain, rendering adolescents vulnerable to mental health problems, including depressive symptoms [
2]. However, the onset of depressive symptoms in adolescence has long-lasting effects on the adolescents’ physical and brain development and may be a significant risk factor for clinical depression later, leading to serious social and educational impairments [
3]. However, the pathological mechanism of depressive symptoms has not been adequately studied.
Evidence suggests that the dysregulated and dysfunctional stress response system (i.e., hypothalamic-pituitary-adrenal (HPA) axis activity and glucocorticoid receptor (GR) sensitivity) has been one of the potential biological mechanisms of depression [
4]. Meanwhile, the FK506 binding protein 51 (FKBP51) is the co-chaperone of heat shock protein (Hsp) 90 and GR, which can inhibit GR sensitivity to regulate the HPA axis and is highly expressed after stress exposure [
5]. Then, the
FKBP5 gene locating on chromosome 6p21.31 (GRCh38), which encodes FKBP51 protein, is an essential regulatory in the HPA stress regulation system [
6].
Since the
FKBP5 gene may be involved in the process of depressive symptoms development, a previous animal study has found a relevant role of the
FKBP5 gene in modulating GR sensitivity and enhancing negative glucocorticoid feedback within the HPA axis through mice model lacking the
FKBP5 gene (51KO mice) [
7]. Human genetic studies have also reported significant associations between
FKBP5 variants and depressive symptoms [
8‐
11], although the results are inconsistent [
12,
13]. For instance, Shimasaki et al. reported a positive association between rs1360780 and depressive state [
14]; Scheuer et al. did not find any significant associations of the five
FKBP5 single-nucleotide polymorphisms (SNPs) with the risk of depression, including rs1360780, rs3800373, rs9296158, rs9470080, and rs4713916) [
15].
Moreover, besides genetics, DNA methylation is an epigenetic modification that regulates gene expression without changing the DNA sequence [
16]. DNA methylation changes can affect gene expression related to the stress regulation system, which has been reported to play a vital role in the pathogenesis of mental disorders [
17]. Prior evidence has shown that alteration in DNA methylation of the
FKBP5 gene may be associated with mental disorders such as depression or depressive symptoms [
18], which remains to be studied.
It has been widely reported that both genetic factors and environmental stressors play a role in the pathogenesis of depressive symptoms. A recent study showed the heritability of 40% for depression in a young adult cohort [
19], suggesting genetic factors may interplay with environmental stressors to contribute to risks of depressive symptoms. Previous evidence suggests that the interactions between environmental stressors and
FKBP5 rs3800373/ rs9296158/ rs1360780/ rs9470080 were statistically significant in a sample of clinically depressed adolescents [
13], and the interaction effects of childhood physical abuse and
FKBP5 rs3800373/ rs1360780/ rs4713916 on depressive symptoms in Chinese adolescents were significant [
20]. There is evidence that DNA methylation of the
FKBP5 gene is modified by external environmental factors [
18]. Furthermore, it has been suggested that childhood trauma exposure interacts with the
FKBP5 T allele could lead to reduced methylation in intron 7 of the
FKBP5 gene, which may affect depressive symptoms [
21].
Although adolescents may experience many environmental stressors, parenting style (referring to general patterns of parental behavior) is critically important for adolescent health [
22], especially in a developmental period characterized by a rapid elevation in depressive symptoms. Based on the Baumrind’s theory, negative parenting style (e.g., authoritarian or neglectful parenting style) can be categorized as a significant environmental stressor. Previous evidence also suggested that authoritarian and neglectful parenting styles were associated with higher depressive symptoms in adolescents [
23,
24]. However, few studies considered the interaction effects between parenting style and
FKBP5 SNPs on depressive symptoms, particularly among adolescents. Scarce studies examined the role of parenting style in influencing
FKBP5 DNA methylation and depressive symptoms in adolescents. Therefore, the aims of this nested case-control study among Chinese adolescents were twofold, to investigate the association of
FKBP5 genetic and epigenetic variation with depressive symptoms among Chinese adolescents and to investigate the potential role of parenting style on these associations.
Results
Table
1 shows the characteristics of the sample. In the students with depressive symptoms (cases), the median age was 13.0 (interquartile range: 13.0 to 15.0) years, the proportion of females was 66.7%, and the proportion of students living with a single parent was 17.5%. In the students without depressive symptoms (controls), the median age was 13.0 (interquartile range: 13.0 to 14.0) years, the proportion of females was 40.7%, and the proportion of students living with a single parent was 8.5%. The differences between the cases and control group in sex and living arrangement distribution were statistically significant (
P < 0.05). Regarding the parenting style, the proportion of students who reported suffering authoritarian parenting style of the father in cases was 10.8% and in the control group was 3.4%; the proportion of those who reported suffering authoritarian parenting style of the mother in cases was 10.0% and in the control group was 1.7%; the differences of reported parenting style between the cases and control group were statistically significant (
P < 0.05).
Table 1
Sample characteristics between cases and control group
Total | 118 (100) | 120 (100) | |
Age, median (interquartile range), year | 13.0 (13.0 to 14.0) | 13.0 (13.0 to 15.0) | 0.118 |
Sex |
Boy | 70 (59.3) | 40 (33.3) | < 0.001 |
Girl | 48 (40.7) | 80 (66.7) | |
Living arrangement |
Living with both parents | 103 (88.0) | 86 (71.7) | 0.006 |
Living with a single parent | 10 (8.5) | 21 (17.5) | |
Living with others | 4 (3.4) | 13 (10.8) | |
Missing data | 1 | | |
Morning serum total cortisol, median (interquartile range), nmol/L | 224.8 (155 to 318) | 197.6 (147.9 to 290.8) | 0.152 |
Parenting style of the father |
Permissive | 81 (68.6) | 67 (55.8) | < 0.001 |
Authoritative | 32 (27.1) | 25 (20.8) | |
Authoritarian | 4 (3.4) | 13 (10.8) | |
Neglectful | 1 (0.8) | 15 (12.5) | |
Parenting style of the mother |
Permissive | 100 (84.7) | 78 (65.0) | 0.001 |
Authoritative | 16 (13.6) | 24 (20.0) | |
Authoritarian | 2 (1.7) | 12 (10.0) | |
Neglectful | 0 | 6 (5.0) | |
The genotype frequency distributions of the
FKBP5 polymorphisms in the cases and control group are shown in
Table S1. As shown in Table
2, without adjusting for other variables, only rs7757037, rs2817032, and rs2817035 were associated with depressive symptoms under the codominant model and dominant model (even after further correction for multiple testing,
q < 0.10). After adjusting for age, gender, living arrangement, and morning cortisol level, a significant association between rs7757037 and depressive symptoms was found in the codominant model (AG vs. GG; adjusted odds ratio [AOR] = 2.56, 95% CI = 1.13–5.78,
q < 0.10) and the dominant model (AA+AG vs. GG; AOR = 2.38, 95% CI = 1.11–5.12,
q < 0.10); rs2817032 polymorphism was associated with depressive symptoms in the codominant model (TT vs. CC; AOR = 3.63, 95% CI = 1.28–10.25,
q < 0.10 & TC vs. CC; AOR = 4.01, 95% CI = 1.35–11.89,
q < 0.10) and dominant model (TT + TC vs. CC; AOR = 3.76, 95% CI = 1.36–10.38,
q < 0.10); rs2817035 was also associated with depressive symptoms in the codominant model (GG vs. AA; AOR = 2.93, 95% CI = 1.08–7.96,
q < 0.10) and dominant model (GG + GA vs. AA, AOR = 2.78, 95% CI = 1.05–7.36,
q < 0.10). However, after further adjusting for the father’s or mother’s parenting style, there are no significant associations of rs7757037, rs2817032, and rs2817035 with depressive symptoms (
P > 0.05; after further correction for multiple testing,
q > 0.10).
Table S2 shows that the haplotype frequencies were not significantly different between the cases and the controls (
P > 0.05).
Table 2
Main effects of the FKBP5 polymorphisms on depressive symptoms
rs7757037* |
Codominant model | AA vs. GG | 2.01 (0.94–4.34) | 0.074 | 0.111 | 2.17 (0.93–5.01) | 0.072 | 0.108 | 2.02 (0.86–4.78) | 0.109 | 0.163 | 1.98 (0.85–4.64) | 0.116 | 0.174 |
| AG vs. GG | 2.35 (1.13–4.92) | 0.023 | 0.075** | 2.56 (1.13–5.78) | 0.024 | 0.062** | 2.34 (1.02–5.36) | 0.044 | 0.115 | 2.02 (0.89–4.63) | 0.095 | 0.174 |
Dominant model | AA+AG vs. GG | 2.20 (1.10–4.39) | 0.025 | 0.075** | 2.38 (1.11–5.12) | 0.026 | 0.062** | 2.20 (1.01–4.78) | 0.048 | 0.115 | 2.00 (0.93–4.33) | 0.077 | 0.174 |
Recessive model | AA vs. AG + GG | 1.09 (0.63–1.89) | 0.748 | 0.748 | 1.10 (0.61–2.00) | 0.744 | 0.744 | 1.10 (0.60–2.02) | 0.762 | 0.762 | 1.21 (0.66–2.23) | 0.543 | 0.543 |
rs2817032* |
Codominant model | TT vs. CC | 3.01 (1.18–7.70) | 0.022 | 0.075** | 3.63 (1.28–10.25) | 0.015 | 0.060** | 3.12 (1.09–8.89) | 0.034 | 0.115 | 2.90 (1.02–8.27) | 0.046 | 0.174 |
TC vs. CC | 2.77 (1.04–7.35) | 0.041 | 0.086** | 4.01 (1.35–11.89) | 0.012 | 0.060** | 3.16 (1.05–9.55) | 0.041 | 0.115 | 3.09 (1.03–9.24) | 0.044 | 0.174 |
Dominant model | TT + TC vs. CC | 2.91 (1.17–7.27) | 0.022 | 0.075** | 3.76 (1.36–10.38) | 0.011 | 0.060** | 3.13 (1.12–8.74) | 0.029 | 0.115 | 2.97 (1.07–8.25) | 0.037 | 0.174 |
Recessive model | TT vs. TC + CC | 1.36 (0.81–2.28) | 0.243 | 0.265 | 1.24 (0.71–2.15) | 0.456 | 0.497 | 1.29 (0.73–2.29) | 0.385 | 0.420 | 1.22 (0.69–2.16) | 0.501 | 0.543 |
rs2817035* |
Codominant model | GG vs. AA | 2.55 (1.03–6.32) | 0.043 | 0.086** | 2.93 (1.08–7.96) | 0.035 | 0.069** | 2.49 (0.90–6.86) | 0.079 | 0.158 | 2.37 (0.86–6.54) | 0.096 | 0.174 |
GA vs. AA | 2.07 (0.80–5.37) | 0.135 | 0.180 | 2.52 (0.88–7.20) | 0.085 | 0.113 | 2.05 (0.70–5.99) | 0.188 | 0.251 | 2.03 (0.70–5.90) | 0.194 | 0.259 |
Dominant model | GG + GA vs. AA | 2.36 (0.98–5.72) | 0.056 | 0.096** | 2.78 (1.05–7.36) | 0.040 | 0.069** | 2.32 (0.86–6.25) | 0.095 | 0.163 | 2.24 (0.84–6.02) | 0.110 | 0.174 |
Recessive model | GG vs. GA + AA | 1.47 (0.87–2.47) | 0.151 | 0.181 | 1.45 (0.83–2.54) | 0.197 | 0.236 | 1.44 (0.81–2.57) | 0.219 | 0.263 | 1.38 (0.77–2.46) | 0.275 | 0.330 |
Parenting style of the father |
Authoritarian | | 1.00 (reference) | | | 1.00 (reference) | | | | | | | | |
Permissive | | 0.26 (0.08–0.82) | 0.021 | NA | 0.19 (0.06–0.66) | 0.009 | NA | NA | NA | NA | NA | NA | NA |
Authoritative | | 0.24 (0.07–0.83) | 0.024 | NA | 0.22 (0.06–0.82) | 0.023 | NA | NA | NA | NA | NA | NA | NA |
Neglectful | | 4.62 (0.46–46.67) | 0.195 | NA | 3.15 (0.29–34.59) | 0.348 | NA | NA | NA | NA | NA | NA | NA |
Parenting style of the mother |
Authoritarian | | 1.00 (reference) | | | 1.00 (reference) | | | | | | | | |
Permissive | | 0.13 (0.03–0.60) | 0.009 | NA | 0.11 (0.02–0.53) | 0.006 | NA | NA | NA | NA | NA | NA | NA |
Authoritative | | 0.25 (0.05–1.27) | 0.095 | NA | 0.22 (0.04–1.21) | 0.081 | NA | NA | NA | NA | NA | NA | NA |
Neglectful | | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA |
Table
3 depicts the interaction effects between
FKBP5 polymorphisms and parenting style on depressive symptoms. After adjusting for age, gender, living arrangement, and morning cortisol level, significant interactions between rs7757037 and the father’s parenting style were found in the codominant model (AG vs. GG;
P = 0.043) and dominant model (AA+AG vs. GG;
P = 0.043). However, the gene-environment interactions were not significant after correcting for multiple testing.
Table 3
Interaction effects between FKBP5 polymorphisms and parenting style on depressive symptoms
rs7757037 |
rs7757037 × parenting style of the father |
Codominant model | AA vs. GG | 5.35 (1.15–24.8) | 0.032 | 4.62 (0.90–23.85) | 0.067 |
AG vs. GG | 6.04 (1.36–26.94) | 0.018* | 5.13 (1.05–25.06) | 0.043 |
Dominant model | AA+AG vs. GG | 5.78 (1.34–24.96) | 0.019* | 4.94 (1.05–23.27) | 0.043 |
Recessive model | AA vs. AG + GG | 1.05 (0.51–2.18) | 0.890 | 1.06 (0.47–2.40) | 0.889 |
rs7757037 × parenting style of the mother |
Codominant model | AA vs. GG | 0.70 (0.11–4.43) | 0.702 | 0.22 (0.03–1.65) | 0.139 |
AG vs. GG | 0.72 (0.12–4.21) | 0.715 | 0.26 (0.04–1.75) | 0.165 |
Dominant model | AA+AG vs. GG | 0.71 (0.13–4.02) | 0.703 | 0.25 (0.04–1.60) | 0.142 |
Recessive model | AA vs. AG + GG | 0.87 (0.32–2.36) | 0.783 | 0.67 (0.22–2.05) | 0.478 |
rs2817032 |
rs2817032 × parenting style of the father |
Codominant model | TT vs. CC | NA | NA | NA | NA |
TC vs. CC | NA | NA | NA | NA |
Dominant model | TT + TC vs. CC | NA | NA | NA | NA |
Recessive model | TT vs. TC + CC | 1.10 (0.56–2.15) | 0.784 | 1.04 (0.49–2.21) | 0.912 |
rs2817032 × parenting style of the mother |
Codominant model | TT vs. CC | NA | NA | NA | NA |
TC vs. CC | NA | NA | NA | NA |
Dominant model | TT + TC vs. CC | NA | NA | NA | NA |
Recessive model | TT vs. TC + CC | 0.98 (0.37–2.57) | 0.969 | 0.61 (0.21–1.79) | 0.372 |
rs2817035 |
rs2817035 × parenting style of the father |
Codominant model | GG vs. AA | 7.60 (0.71–81.21) | 0.094 | 8.30 (0.70–97.85) | 0.093 |
GA vs. AA | 7.50 (0.70–80.67) | 0.097 | 7.95 (0.66–95.40) | 0.102 |
Dominant model | GG + GA vs. AA | 7.43 (0.71–77.64) | 0.094 | 8.14 (0.71–93.65) | 0.093 |
Recessive model | GG vs. GA + AA | 1.10 (0.56–2.14) | 0.787 | 1.15 (0.54–2.45) | 0.714 |
rs2817035 × parenting style of the mother |
Codominant model | GG vs. AA | NA | NA | NA | NA |
GA vs. AA | NA | NA | NA | NA |
Dominant model | GG + GA vs. AA | NA | NA | NA | NA |
Recessive model | GG vs. GA + AA | 1.19 (0.46–3.05) | 0.722 | 0.90 (0.32–2.58) | 0.850 |
As shown in
Table S3, we observed no significant differences in the methylation levels of the selected
FKBP5 CpG sites between the cases and the control group (all
P > 0.05). Additionally, there were no significant interactions between
FKBP5 gene methylation status and parenting styles on depressive symptoms observed in this study (all
P > 0.05, Table
4).
Table 4
Interaction effects between FKBP5 gene methylation status and parenting style on depressive symptoms
Parenting style of the father× |
FKBP5–12 CpG 1 | 0.653 |
FKBP5–12 CpG 2 | 0.974 |
FKBP5–12 CpG 3 | 0.414 |
FKBP5–12 CpG 4 | 0.761 |
FKBP5–12 CpG 5.6.7 | 0.951 |
FKBP5–12 CpG 8 | 0.630 |
FKBP5–12 CpG 9 | 0.887 |
FKBP5–12 CpG 10.11 | 0.942 |
FKBP5–12 CpG 12 | 0.232 |
FKBP5–12 CpG 13 | 0.463 |
FKBP5–12 CpG 14 | 0.599 |
FKBP5–12 CpG 15 | 0.491 |
FKBP5–12 CpG 17.18.19 | 0.505 |
FKBP5–12 CpG 20 | 0.761 |
Parenting style of the mother× |
FKBP5–12 CpG 1 | 0.951 |
FKBP5–12 CpG 2 | 0.661 |
FKBP5–12 CpG 3 | 0.575 |
FKBP5–12 CpG 4 | 0.211 |
FKBP5–12 CpG 5.6.7 | 0.230 |
FKBP5–12 CpG 8 | 0.217 |
FKBP5–12 CpG 9 | 0.852 |
FKBP5–12 CpG 10.11 | 0.818 |
FKBP5–12 CpG 12 | 0.063 |
FKBP5–12 CpG 13 | 0.205 |
FKBP5–12 CpG 14 | 0.486 |
FKBP5–12 CpG 15 | 0.498 |
FKBP5–12 CpG 17.18.19 | 0.766 |
FKBP5–12 CpG 20 | 0.211 |
Discussion
Considering that the stress-related gene
FKBP5 may play a prominent role in depressive symptoms, this study investigated
FKBP5 polymorphisms and methylations as potential candidates for gene-environment influences on depressive symptoms in an adolescent sample. Our findings suggested that among the selected 14 SNPs, only
FKBP5 rs7757037, rs2817032, and rs2817035 were associated with the increased risk of depressive symptoms in the codominant model and dominant model with and without adjusting for sociodemographic characteristics. Similarly, Piechaczek et al. reported that no main genetic effects of the five SNPs (rs3800373, rs9296158, rs1360780, rs9470080, and rs4713916) on depression were found [
13]; Lou et al. reported that rs7757037 of
FKBP5 was associated with depression in Chinese systemic lupus erythematosus patients [
40] in dominant model. However, this finding was inconsistent with a study among patients with coronary artery disease, indicating rs2817032 was not associated with depressive symptoms among those patients [
41]. The diversity of populations, which might result in various gene sensitivity, may explain the discrepancy of genotype models, while this study focused on Chinese adolescents.
Previous evidence has suggested that parenting style was one of the most significant environmental stressors influencing their child’s growth [
22]. Consistent with prior studies [
24,
42], the protective role of the father’s permissive and authoritative parenting style on the development of depressive symptoms among Chinese adolescents was observed. Moreover, this study found that the significant genetic main effects of
FKBP5 rs7757037, rs2817032, and rs2817035 were not significant after adjusting for the parenting style of the father or mother, respectively. These findings were in line with most prior studies, which demonstrated no main genetic effects predicting case-control status after adjusting for other variables [
12,
13,
15]; indicating that genetic factors may have to interact with environmental stressors to elicit depressive symptoms [
19].
Considering that the
FKBP5 gene plays a vital role in regulating the HPA-axis and is implicated in depressive symptoms [
18], it seems appropriate to study the effect of the
FKBP5 gene in the context of parenting style as an environmental stressor. Extending previous evidence, a novel aspect of this study was that the influences of the parenting style of father/mother (reflecting more stable living background) and their interactions with
FKBP5 polymorphisms on adolescent depressive symptoms were explored. In contrast, much of the previous literature on the gene-environment interactions at the
FKBP5 locus in the context of depressive symptoms mainly focused on adverse or traumatic life events [
15,
20]. In this study, without adjusting for sociodemographic variables, significant interactions between
FKBP5 rs7757037 and the father’s parenting style were first observed in the codominant and dominant model, even correcting for multiple testing. These results might be explained by the diathesis-stress model of depressive symptoms [
43], which indicated that
FKBP5 rs7757037 carriers might exhibit a heightened HPA response activity and be more likely to be implicated in the risk for depressive symptoms when experiencing negative parenting styles. However, based on multiple testing corrections, these interaction effects did not significantly predict depressive symptoms after adjusting for sociodemographic variables. These interactions reached nominal significance, and the relatively small sample size in the present study needs to be considered. It would be significant to follow up on this finding in future studies using larger sample sizes. Besides, this finding may also reflect that a single environmental stressor (i.e., parenting style in this study) may not be potent enough to elicit depressive symptoms in adolescence, and other sociodemographic stressors may influence the effects of the single one environmental stress.
Additionally,
FKBP5 epigenetic changes induced by environmental stressors may also be associated with the risk of depressive symptoms [
44]. Considering parenting style may affect the developing brain through leading to changes in methylation levels of
FKBP5, this study also compared the difference of
FKBP5 methylation levels between students with and without depressive symptoms, and investigated the interactions between
FKBP5 methylation status and parenting style. However, no significant findings were observed. Similarly, Klinger-König et al. reported there were no significant effects of
FKBP5 methylation or the interaction between
FKBP5 methylation and childhood maltreatment on depressive symptoms [
45]. Höhne et al. showed that no significant difference of
FKBP5 DNA methylation in intron 7 between subjects with a lifetime history of depression and healthy controls was observed [
46]. Bustamante et al. also reportedly did not observe any association of
FKBP5 methylation levels in intron 7 or intron 2 with depressive symptoms [
47]. These results might be related to the complex relationship between parenting style,
FKBP5 methylation, and depressive symptoms, highlighting that multiple factors may contribute to the development of depressive symptoms following exposure to different parenting styles. Moreover, parenting style exposures have been shown to be long-lasting, and they may not only influence depressive symptoms through the
FKBP5 methylation pathway.
To our knowledge, the present study is the first nested case-control study to explore the associations of
FKBP5 genetic and epigenetic variation with depressive symptoms among Chinese adolescents in the context of parenting style. However, several limitations should be noted. First, only the
FKBP5 gene was examined in this study by a hypothesis-driven approach. Considering this study only focused on the effects of the
FKBP5 gene, other potential genes with implications in depressive symptoms (e.g.,
BDNF or
NR3C1 gene) were not considered, and we would like to explore the effects of other genes on depressive symptoms in our future study. Second, although parenting style and depressive symptoms were measured by self-reported, which may lead to self-report bias, self-reports remain a common and accepted method. Third, considering the questionnaire length, parenting style was not assessed by the scales like the Egna Minnen Beträffande Uppfostran (EMBU) in this study, then the lack of evaluating psychometric properties for the parenting style measure in this study may be a limitation. Fourth, although previous studies have used a similar sample size to explore the associations between the
FKBP5 gene and depressive symptoms or depression [
45,
47], the sample size in the present study is relatively small, which may imply insufficient statistical power these findings.
Conclusions
This study suggests significant relationships of FKBP5 rs7757037, rs2817032, and rs2817035 with depressive symptoms without adjusting for parenting style and observes a nominally significant interaction between FKBP5 rs7757037 and parenting style of the father on depressive symptoms. However, there was no significant association between FKBP5 CpG methylation status and the interactions between FKBP5 CpG methylation and parenting style with depressive symptoms. Therefore, this work suggests that parenting style, almost experiencing by each adolescent, can be targeted in prevention strategies, and a particular focus should be placed on adolescents who suffer negative parenting styles. Moreover, this study also indicates that FKBP5 variation, not DNA methylation, may be more sensitive in moderating the effects of parenting style stressors on depressive symptoms, especially for the negative parenting style of the father, even though the evidence under the mechanism is deficient now. Further studies to investigate the underlying mechanism are warranted.
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