Glucocorticoid Receptor-Related Genes: Genotype and Brain Gene Expression Relationships to Suicide and Major Depressive Disorder

Abstract

Introduction We tested the relationship between genotype, gene expression and suicidal behavior and MDD in live subjects and postmortem samples for three genes, associated with the hypothalamic-pituitary-adrenal axis, suicidal behavior and major depressive disorder (MDD); FK506 binding protein 5 (FKBP5), Spindle and kinetochore-associated protein 2 (SKA2) and Glucocorticoid Receptor (NR3C1). Materials and Methods Single-nucleotide polymorphisms (SNPs) and haplotypes were tested for association with suicidal behavior and MDD in a live (N=277) and a postmortem sample (N=209). RNA-seq was used to examine gene and isoform-level brain expression postmortem (Brodmann Area 9) (N=59). Expression quantitative trait loci (eQTL) relationships were examined using a public database (UK Brain Expression Consortium). Results We identified a haplotype within the FKBP5 gene, present in 47% of the live subjects, that was associated with increased risk of suicide attempt (OR=1.58, t=6.03, p=0.014). Six SNPs on this gene, three SNPs on SKA2 and one near NR3C1 showed before-adjustment association with attempted suicide, and two SNPs of SKA2 with suicide death, but none stayed significant after adjustment for multiple testing. Only the SKA2 SNPs were related to expression in the prefrontal cortex. One NR3C1 transcript had lower expression in suicide relative to non-suicide sudden death cases (b=-0.48, SE=0.12, t=-4.02, adjusted p=0.004). Conclusion We have identified an association of FKBP5 haplotype with risk of suicide attempt and found an association between suicide and altered NR3C1 gene expression in the prefrontal cortex. Our findings further implicate hypothalamic pituitary axis dysfunction in suicidal behavior.

Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder

“…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.…”

“…[56] 9. [57]. All FKBP5 transcripts have been collated to show exons (black vertical lines), introns (black horizontal lines) and untranslated regions (black boxes).…”

“…They further identified a haplotype block with increased risk of suicidal behavior comparing depressed suicide attempters and depressed controls. However, these findings were not corrected for multiple testing [57]. 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].…”

Blunted HPA axis activity prior to suicide attempt and increased inflammation in attempters

“…However, FKBP5 mRNA was consistently reduced (ES=−0.29) and SKA2 mRNA consistently increased in SI in the full and reduced samples (ES=0.35 and 0.40, respectively). Lower FKBP5 mRNA has been reported in brains of suicides and in subjects with PTSD (Perez-Ortiz et al, 2013; Sarapas et al, 2011; Yin et al, 2016); and FKBP5 polymorphisms have been previously associated with suicidal events in adolescents (Brent et al, 2010). Reduced SKA2 expression is also reported in postmortem brains of suicides and in patients with suicidal ideation and behavior (Guintivano et al, 2014; Niculescu et al, 2015; Pandey et al, 2016).…”

“…Reduced hippocampal GR mRNA is reported in brains of people who died by suicide and suicides with history of abuse (Labonte et al, 2012; McGowan et al, 2009; Sequeira et al, 2012). Studies in postmortem brains and living subjects have also implicated the expression of GR-related genes, specifically, SKA2 and FKBP5 , in suicidal ideation and behavior (Guintivano et al, 2014; Niculescu et al, 2015; Pandey et al, 2016; Perez-Ortiz et al, 2013; Yin et al, 2016). …”