Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Abstract

FKBP5 is a critical component of the Hypothalamic-Pituitary-Adrenal (HPA) axis, a system which regulates our response to stress. It forms part of a complex of chaperones, which inhibits binding of cortisol and glucocorticoid receptor translocation to the nucleus. Variations in both the HPA axis and FKBP5 have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near FKBP5 in 476 bipolar disorder suicide attempters and 473 bipolar disorder non-attempters. Following stringent quality control checks, we performed single-variant, gene-level and haplotype tests on the resulting 481 variants. Secondary analyses investigated whether sex-specific variations in FKBP5 increased the risk of attempted suicide. One variant, rs141713011, showed an excess of minor alleles in suicide attempters that was statistically significant following correction for multiple testing (Odds Ratio = 6.65, P-value = 7.5 x 10−4, Permuted P-value = 0.038). However, this result could not be replicated in an independent cohort (Odds Ratio = 0.90, P-value = 0.78). Three female-specific and four male-specific variants of nominal significance were also identified (P-value < 0.05). The gene-level and haplotype association tests did not produce any significant results. This comprehensive study of common and rare variants in FKBP5 focused on both regulatory and coding regions in relation to attempted suicide. One rare variant remained significant following correction for multiple testing but could not be replicated. Further investigation is required in larger sample sets to fully elucidate the association of this variant with suicidal behavior.

DNA methylation of FKBP5 in South African women: associations with obesity and insulin resistance

“…While FKBP5 has been extensively studied in the context of neuropsychiatric diseases [ 5 , 36 – 39 ], several recent studies have uncovered a metabolic role for this gene [ 40 ]. Indeed, preclinical studies using animal models have demonstrated that deletion of the FKBP5 gene protects mice from diet-induced obesity and hepatic steatosis, and pharmacological inhibition of FKBP5 improves their metabolic health [ 41 , 42 ].…”

<b><i>FKBP5</i></b> Gene Variants May Modulate Depressive Features in Bipolar Disorder

“…The HPA axis is a tightly controlled molecular cascade in which many proteins are involved. One of the critical components of the HPA axis is the co-chaperone FK506 binding protein 5 (FKBP5) [19]. …”

Genes involved in stress response influence lithium efficacy in bipolar patients

“…One of the most potent regulators in GR signaling is a co‐chaperone protein encoded by the FK506 binding protein ( FKBP) 5 gene. Previous studies have shown that the genetic variation in co‐chaperone genes (e.g., FKBP5 ) influences the susceptibility to MDD and bipolar disorder …”

“…Previous studies have shown that the genetic variation in co-chaperone genes (e.g., FKBP5) influences the susceptibility to MDD and bipolar disorder. [10][11][12][13][14] Variations in HPA axis regulation may result from different genetic backgrounds but also from environmental stimuli such as stressful life events, thus affecting the response to antidepressant treatment. [15][16][17] In regard to lithium, our previous study showed that polymorphism within the GR (nuclear receptor subfamily 3 group C member 1 [NR3C1]) gene is associated with lithium response in bipolar patients, 18 and a recent study in an animal model confirmed that lithium treatment may also modify the HPA axis response to stressful life events.…”