Association between &lt;b&gt;&lt;i&gt;FKBP5&lt;/i&gt;&lt;/b&gt; Functional Polymorphisms and Completed Suicide

Fudalej, Sylwia; Kopera, Maciej; Wołyńczyk-Gmaj, Dorota; Fudalej, Marcin; Krajewski, Paweł; Wasilewska, Krystyna; Szymański, Konrad M.; Chojnicka, Izabela; Podgórska, Anna; Wojnar, Marcin; Płoski, Rafał

doi:10.1159/000441659

Cited by 31 publications

(24 citation statements)

References 38 publications

(49 reference statements)

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“…One variant of particular interest to the field, rs3800373 [9–14, 56, 57] has repeatedly been associated with suicidal behavior, but did not show association in our study (P-value = 0.52). This may be due to our case-only approach, which differs from the trio or case-control designs used by others.…”

Section: Discussioncontrasting

confidence: 89%

“…A Japanese study identified a statistically significant haplotype block with two FKBP5 variants (rs1360780 and rs3800373) in suicide completers, but did not find any single-variant associations [12]. A second, larger cohort of suicide completers was also genotyped for rs1360780 and rs3800373, and an association was found with rs3800373 [56]. It must be noted that the main limitations of all these studies was the small sample size and limited genotyping data.…”

Section: Discussionmentioning

confidence: 99%

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Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Breen¹,

Gaynor²,

Monson³

et al. 2016

PLoS ONE

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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.

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Section: Discussioncontrasting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Breen¹,

Gaynor²,

Monson³

et al. 2016

PLoS ONE

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“…The comparison group consisted of 450 individuals tested for disputed paternity at the Department of Forensic Medicine as described previously . The male frequency was 52.9% ( n = 238), mean age was 36.9 ± 10.0 years.…”

Section: Methodsmentioning

confidence: 99%

An association between genetic variation in the glutamatergic system and suicide attempts in alcohol-dependent individuals

et al. 2017

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“…Overwhelmingly these studies demonstrate the importance of FKBP51 in the way humans adapt or maladapt to stressful life events. In other words, FKBP51 is key to the gene‐environment interactions that not only change HPA axis settings , but may also lead to stress‐related diseases such as PTSD , depression , suicidality , bipolar disorder , and addiction . The evidence supporting the clinical role of the GR‐FKBP51 system has recently been reviewed much more extensively .…”

Section: Fkbp51 Shapes Stress Adaptation In Mice and Humansmentioning

confidence: 99%

FK506 binding protein 51 integrates pathways of adaptation

Rein

2016

BioEssays

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This review portraits FK506 binding protein (FKBP) 51 as "reactivity protein" and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co-chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding in response to proteotoxic stress. In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion. Also see the video abstract here.

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Association between <b><i>FKBP5</i></b> Functional Polymorphisms and Completed Suicide

Cited by 31 publications

References 38 publications

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

An association between genetic variation in the glutamatergic system and suicide attempts in alcohol-dependent individuals

FK506 binding protein 51 integrates pathways of adaptation

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