Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Marie E Breen; Sophia C Gaynor; Eric T Monson; Kelly de Klerk; Meredith G Parsons; Terry A Braun; Adam P DeLuca; Peter P Zandi; James B Potash; Virginia L Willour

doi:10.1371/journal.pone.0169158

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Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Journal article

Open access

Peer reviewed

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

Marie E Breen, Sophia C Gaynor, Eric T Monson, Kelly de Klerk, Meredith G Parsons, Terry A Braun, Adam P DeLuca, Peter P Zandi, James B Potash and Virginia L Willour

PloS one, Vol.11(12), pp.e0169158-e0169158

2016

DOI: 10.1371/journal.pone.0169158

PMCID: PMC5193409

PMID: 28030643

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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.

Haplotypes - genetics

Suicide, Attempted

Humans

Polymorphism, Single Nucleotide - genetics

Female

Genotype

Male

High-Throughput Nucleotide Sequencing

Bipolar Disorder - genetics

Case-Control Studies

Bipolar Disorder - psychology

Tacrolimus Binding Proteins - genetics

Details

Title: Subtitle: Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder
Creators: Marie E Breen - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Sophia C Gaynor - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Eric T Monson - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Kelly de Klerk - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Meredith G Parsons - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Terry A Braun - Department of Biomedical Engineering, University of Iowa College of Engineering, Iowa City, Iowa, United States of America
Adam P DeLuca - Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Peter P Zandi - Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
James B Potash - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Virginia L Willour - Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.11(12), pp.e0169158-e0169158
DOI: 10.1371/journal.pone.0169158
PMID: 28030643
PMCID: PMC5193409
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 MH079240 / NIMH NIH HHS T32 GM007337 / NIGMS NIH HHS
Language: English
Date published: 2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Psychiatry; Pathology; Iowa Neuroscience Institute; Center for Bioinformatics and Computational Biology; Ophthalmology and Visual Sciences
Record Identifier: 9984064589802771

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