Analysis of the association of MIR124-1 and its target gene RGS4 polymorphisms with major depressive disorder and antidepressant response

Abstract

Background

Increasing evidence has indicated that dysfunction of miR-124 and target gene regulator of G protein signaling 4 (RGS4) may be involved in the etiology and treatment of major depressive disorder (MDD). However, the molecular mechanisms are not fully understood. This study aimed to investigate whether common genetic variations in these two genes are associated with MDD and therapeutic response to antidepressants in the Chinese population.

Methods

Three polymorphisms including rs531564 (a functional single-nucleotide polymorphism [SNP] in MIR124-1), rs10759 (a microRNA-binding site SNP in RGS4), and rs951436 (a promoter SNP in RGS4) were genotyped in 225 Chinese MDD patients and 436 controls. Among the MDD patients, 147 accepted antidepressant treatment for 8 weeks with therapeutic evaluation at baseline, week 2, week 4, week 6, and week 8 using the 17-item Hamilton Rating Scale for Depression. Multifactor dimensionality reduction (MDR) was used to identify gene–gene interactions.

Results

No significant association with MDD was discovered in single-SNP analyses. However, by MDR analysis, the three-locus model of gene–gene interaction was the best for predicting MDD risk. In pharmacogenetic study, a significant association was found in genotypic frequencies of rs951436 between the remitter and non-remitter groups (p=0.026, correction p=0.078). For further analysis, the rs951436 heterozygote carriers had threefold probabilities of achieving clinical complete remission (odds ratio =3.00, 95% confidence interval =1.33–6.76, p=0.007, correction p=0.021) as compared with rs951436 homozygotes (AA+CC) after 8 weeks of treatment.

Conclusion

An interaction effect of MIR124-1 and RGS4 polymorphisms may play a more important role than individual factors for MDD development. Moreover, RGS4 gene polymorphisms may be associated with antidepressant response among the Han population.

Keywords:

• polymorphisms
• MIR124-1
• regulator of G protein signaling 4
• depression
• antidepressant
• gene–gene interaction

Supplementary material

Figure S1 Percent reduction of Hamilton Rating Scale for Depression (HAMD) scores of antidepressant treatment across genotypes of rs10759 (A), rs531563 (B), and rs951436 (C). No significant differences were found between the three polymorphisms and antidepressant.

Acknowledgments

We gratefully acknowledge the skillful technical support of Mr Dongxiang Wang and Mr Songzhi Zhang. We also thank the patients and healthy volunteers for their participation. This study was supported by grants from the Collaborative Innovation Center for Translational Medicine at Shanghai Jiao Tong University School of Medicine (TM201506, TM201624), National Major Project for IND (2018ZX09734005), and the Programs Foundation of Shanghai Mental Health Center (2017-QH-02).

Disclosure

The authors report no conflicts of interest in this work.