The Association of FKBP5 Gene Methylation, Adolescents’ Sex, and Depressive Symptoms among Chinese Adolescents: A Nested Case-Control Study

Background: Depressive symptoms among adolescents are a serious health concern around the world. Altered DNA methylation in the FK506 binding protein 5 ( FKBP5 ) gene has been reported to regulate stress response, which has been reported to be closely associated with depressive symptoms. However, most of the contributing studies have been conducted among adults and relatively few studies have considered the effect of disparate social influences and sex differences on the DNA methylation of FKBP5 in persons with depressive symptoms. The present study aimed to test the associations of FKBP5 DNA methylation and depressive symptoms among adolescents and explore possible sex differences in the foregoing associations. Methods: : This study was conducted using a nested case-control design within a longitudinal cohort study from January 2019 to December 2019. Adolescents aged 12 to 17 years from 69 classes in 10 public high schools located in Guangdong province of China participated in this research. Students with depressive symptoms at baseline and follow-up were randomly selected as the case group, and those without depressive symptoms were treated as the control group. Our study finally included 87 cases and 151 controls matched for age. Results: : The overall DNA methylation trend of FKBP5 CpG sites in the case group was lower in comparison to the control group. Compared to healthy controls, lower methylation percentage of FKBP5 -12 CpG 1 was observed in adolescents with depressive symptoms after adjusting for covariates (case: 0.94 ± 2.00, control: 0.47 ± 0.92; F = 5.41, P = 0.021). However, the hypomethylation of FKBP5 -12 CpG 1 was approaching significance after adjustment for social-environmental factors (aOR = 0.77; P = 0.055), which indicated that hypomethylation of FKBP5 CpG sites may not be an independent risk factor for depressive symptoms in our sample. In addition, in the present study, we were unable to identify sex differences in the association of FKBP5 gene methylation with depressive symptoms. Conclusions: : The decreased methylation level of FKBP5 was observed in adolescents with depressive symptoms. Our results presented here are preliminary and underscore the complex gene-environment interactions relevant to the risk for depressive symptoms.