Dataset Information

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.

SUBMITTER: Breen ME

PROVIDER: S-EPMC5193409 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder.

Breen Marie E ME Gaynor Sophia C SC Monson Eric T ET de Klerk Kelly K Parsons Meredith G MG Braun Terry A TA DeLuca Adam P AP Zandi Peter P PP Potash James B JB Willour Virginia L VL

PloS one 20161228 12

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 ...[more]

PMID: 28030643

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Project description:We conducted a retrospective investigation of potential clinical, demographic, and neuropsychological risk factors for suicide attempts in patients diagnosed with bipolar disorder.Participants included 67 adult inpatients and outpatients aged 18-60 years meeting DSM-IV criteria for bipolar disorder (bipolar I and II disorders, bipolar disorder not otherwise specified). We assessed demographic factors, mood symptoms, psychosis, trauma history, trait impulsivity, trait aggression, and reasons for living. The primary outcome measures were the Barratt Impulsiveness Scale-version II, Aggression Questionnaire, and 10 cognitive outcome variables. The cognitive outcome variables assessed cognitive performance across several domains, including processing speed, attention, verbal learning, and executive function. Another aspect of cognitive function, decision making, was assessed using the Iowa Gambling Task. The study was conducted from July 2007-July 2009.We found that nonattempters reported significantly higher trait impulsivity scores on the Barratt Impulsiveness Scale compared to attempters (t(57) = 2.2, P = .03) and that, among attempters, lower trait impulsivity score was associated with higher scores of lethality of prior attempts (r(25) = -0.53, P = .01). Analyses revealed no other group differences on demographic, clinical, or neurocognitive variables when comparing attempters versus nonattempters. Regression models failed to identify any significant predictors of past suicide attempt.The largely negative results of our study are particularly important in highlighting the clinical dilemma faced by many clinicians when trying to predict which patients will make serious suicide attempts and which patients are at a lower risk for acting on suicidal thoughts. A limitation of our work is that we examined stable trait measures of impulsivity among a euthymic sample rather than mood state or the impact of mood state on traits. Overall, we conclude that suicidal behavior is extremely difficult to predict, even when comprehensive clinical and neurocognitive information is available.

Dataset Information

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder.

Publications

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder.

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