Regulatory functions of FKBP5 intronic regions associated with psychiatric disorders

• Published in: Journal of psychiatric research 2021-11, Vol.143, p.1-8
• Main Authors: Mendonça, Mariana S., Mangiavacchi, Paula M., Rios, Álvaro.F.L.
• Format: Article
• Language: English
• Subjects: DNA Methylation; Epigenesis, Genetic; FKBP5; HPA axis; Humans; Intronic SNP; Introns; Major depressive disorder; Mental Disorders - genetics; Polymorphism, Single Nucleotide; Post-traumatic stress disorder; Tacrolimus Binding Proteins - genetics
• ISSN: 0022-3956; 1879-1379
• DOI: 10.1016/j.jpsychires.2021.08.014

The FKBP5 gene codifies a co-chaperone protein associated with the modulation of glucocorticoid receptor interaction involved in the adaptive stress response. The FKBP5 intracellular concentration affects the binding affinity of the glucocorticoid receptor (GR) to glucocorticoids (GCs). This gene has glucocorticoid response elements (GREs) located in introns 2, 5 and 7, which affect its expression. Recent studies have examined GRE activity and the effects of genetic variants on transcript efficiency and their contribution to susceptibility to behavioral disorders. Epigenetic changes and environmental factors can influence the effects of these allele-specific variants, impacting the response to GCs of the FKBP5 gene. The main epigenetic mark investigated in FKBP5 intronic regions is DNA methylation, however, few studies have been performed for all GREs located in these regions. One of the major findings was the association of low DNA methylation levels in the intron 7 of FKBP5 in patients with psychiatric disorders. To date, there are no reports of DNA methylation in introns 2 and 5 of the gene associated with diagnoses of psychiatric disorders. This review highlights what has been discovered so far about the relationship between polymorphisms and epigenetic targets in intragenic regions, and reveals the gaps that need to be explored, mainly concerning the role of DNA methylation in these regions and how it acts in psychiatric disease susceptibility. •Intronic regions of FKBP5 gene plays a regulatory function in gene expression.•The SNP rs1360780 presents a functional effect in psychiatric disorders.•The high-risk T allele of rs1360780 has relation with psychiatric disorders, as MDD.•Intronic DNA methylation of FKBP5 act in psychiatric disorders development.•DNA methylation in functional GREs is dependent on the genotype of FKPB5 rs1360780.