Association Between Polymorphisms in the FKBP5 Gene and MDD
It is hypothesized that multiple single nucleotide polymorphisms (SNPs) work together to influence risk of complex neuropsychiatric disorders such as depression.
Human genetic studies reveal a heritability of major depressive disorder (MDD) at approximately 35% to 40%. The use of genome-wide association studies (GWAS) has helped identify multiple common genetic variants, or single nucleotide polymorphisms (SNPs), that influence the risk for depression.
One of the identified candidate genes shown to play a role in conferring vulnerability to MDD is FK506 binding protein 51 (FKBP5), a hypothalamic-pituitary-adrenal (HPA) axis-related gene known to regulate glucocorticoid receptor sensitivity and cortisol levels. More specifically, FKBP5 alters glucocorticoid receptor complex affinity for cortisol and decreases overall glucocorticoid receptor signaling.
The relative success of the genome-wide experiments in detecting causal genes in complex disorder such as depression relies on a sufficiently large sample size. Meta-analysis is a powerful method used to circumvent this major limitation. Also, individual SNPs exert a relatively small effect on overall disease risk, and it is therefore assumed that multiple SNPs work together to influence risk of neuropsychiatric disorders such as depression.
In order to further investigate the association between common variants in FKBP5 and MDD risk, researchers performed a meta-analysis of four common SNPs (rs1360780, rs4713916, rs3800373, and rs755658). They identified seven eligible studies totaling 12 491 individuals diagnosed with MDD and 14 091 typical, healthy controls. The authors removed one of the seven studies, however, after conducting a sensitivity analysis.
Their findings show that certain polymorphisms in FKBP5 are associated with MDD risk. More specifically, the rs1360780 T-allele (Z=2.95, P=0.003, OR=1.062, 95% CI 1.02-1.11) and the rs3800373 C-allele (Z=3.05, P=0.002, OR=1.070, 95% CI 1.02-1.12) were both significantly associated with MDD. However, “No prior individual study has reported a significant association of MDD with either rs1360780 or rs3800373,” they noted. The report was recently published by the Scientific Reports journal.
“Given that the studies included in the meta-analysis involve predominantly individuals of European ancestry, it's difficult to generalize these findings to other ethnic groups,” the authors concluded.
Rao S, Yao Y, Ryan J, et al. Common variants in FKBP5 gene and major depressive disorder (MDD) susceptibility: a comprehensive meta-analysis. Sci Rep. 2016;6:32687.