Abstract:  Glucocorticoid receptor gene (NR3C1), one of the key genes involved in the HPA axis regulation, has been evidenced to have a role in various stress-related physical and mental illnesses. Previous studies concerning NR3C1 polymorphisms and anxiety disorders, however, have mostly been conducted among adult samples and looked into negative environmental variables such as adverse or traumatic life events while examining the gene-environment interactions. There is a dearth of knowledge on how NR3C1 polymorphisms could contribute to adolescent anxiety disorders. The purpose of this study was to examine the genetic variants in NR3C1 and their interaction with paternal and maternal parenting styles in relationship to adolescent anxiety disorders using a Chinese sample. This study adopted a case-control design. Of 3501 adolescents underwent a stepwise clinical screening, 117 who were diagnosed with anxiety disorders (74 females; average age 16.69 ± 1.13 years) and 121 healthy controls (56 female; average age 16.54 ± 1.05 years) were included in this study. Participants’ oral mucosal samples were collected for DNA extraction and three single-nucleotide polymorphisms (SNPs) of the NR3C1 gene (i.e., rs41423247, rs6191, rs6196) were genotyped using MassARRAY system. The Chinese version of Parental Bonding Instrument was used to measure four types of paternal/maternal parenting styles (i.e., warmth, autonomy, overprotection, indifference). Multivariate logistic regressions were performed to examine the main effects of genotypes and parental/maternal parenting styles and their interactions in predicting the presence of anxiety disorders. Results revealed that rs6191 GG genotype, rs6196 AA genotype and rs41423247 GG genotype were associated with decreased risk of anxiety disorders. Higher level of paternal/maternal overprotection and indifference, as well as lower level of paternal warmth, could predict increased risk of anxiety disorders. Moreover, there was a significant interaction between rs41423247 genotypes and maternal warmth in predicting adolescent anxiety disorders; that is, rs41423247 GG genotype was linked with reduced risk of anxiety disorders only when maternal warmth was high. Haplotype analysis revealed three haplotypes with frequencies of > 5% (rs6191-rs6196-rs41423247): GAG, TAC, and TGC. GAG and TGC were respectively associated with decreased and increased risk of anxiety disorders. Maternal warmth and overprotection were found to moderate these effects. GAG would reduce the risk of anxiety disorders only when maternal warmth was high, while TGC would enhance the risk only when maternal overprotection was high. This study is the first to investigate the role of NR3C1 polymorphisms and parenting styles in anxiety disorders among Chinese adolescents. The findings on gene-environment interactions lend support to the vantage sensitivity hypothesis, which propose variation in people’s responsiveness to exclusively positive environmental influences as a function of individual endogenous characteristics. Future research on the epigenetic mechanisms underlying the relationship between NR3C1, parenting styles and adolescent anxiety disorders is warranted, to further explore the disease etiology.

Key words:  anxiety disorders, glucocorticoid receptor gene, parenting styles, gene-environment interaction