Targeted Sequencing of <i>FKBP5</i> in Suicide Attempters with Bipolar Disorder

<div><p>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 <i>FKBP5</i> have been associated with suicidal behavior. We developed a systematic, targeted sequencing approach to investigate coding and regulatory regions in or near <i>FKBP5</i> 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 <i>FKBP5</i> 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 <i>FKBP5</i> 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.</p></div

Haplotype block structures in the <i>FKBP5</i> region.

<p>A collated version of all <i>FKBP5</i> transcripts is represented at the top of the figure. Vertical black lines represent exons, green boxes represent untranslated regions and purple boxes represent intronic regions. The numbered squares display the D’ score, unnumbered squares have a D’ score of 1.0. Three haplotype blocks were generated and are enclosed by black lines. Lines connect the variants to their approximate location within the <i>FKBP5</i> locus.</p

Sex-specific gene-level results using two minor allele thresholds.

<p>Sex-specific gene-level results using two minor allele thresholds.</p

Single-variant results with a P-value < 0.05.

<p>Single-variant results with a P-value < 0.05.</p

Gene-level results using two minor allele thresholds.

<p>Gene-level results using two minor allele thresholds.</p

Schematic of the top variant in the <i>FKBP5</i> gene alongside previous findings.

<p>The top single variant result is displayed below the gene; variants or haplotypes with known associations to suicidal behavior are displayed above the gene. Gray variants were not covered by this study. Numbers represent references: <b>1.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref010" target="_blank">10</a>] <b>2.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref014" target="_blank">14</a>] <b>3.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref055" target="_blank">55</a>] <b>4.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref012" target="_blank">12</a>] <b>5.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref013" target="_blank">13</a>] <b>6.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref011" target="_blank">11</a>] <b>7.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref009" target="_blank">9</a>] <b>8.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref056" target="_blank">56</a>] <b>9.</b> [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0169158#pone.0169158.ref057" target="_blank">57</a>]. All <i>FKBP5</i> transcripts have been collated to show exons (black vertical lines), introns (black horizontal lines) and untranslated regions (black boxes). A transcription factor binding site (TFBS; green box) and DNase hypersensitivity site (purple box) upstream of the top variant are labeled and are not to scale. GRE denotes glucocorticoid receptor response elements (blue boxes) and are not to scale.</p

Haplotype results generated using Haploview.

<p>Haplotype results generated using Haploview.</p